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Zheng Y, Yu X, Li W, Wu F, Gu Y, Liu K, Tao S, Liu Y, Wang Q. HLA is a potent immunoinflammatory target in asymptomatic Alzheimer's disease. Neuroscience 2025; 565:386-398. [PMID: 39571960 DOI: 10.1016/j.neuroscience.2024.11.049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 11/09/2024] [Accepted: 11/18/2024] [Indexed: 12/16/2024]
Abstract
Alzheimer's disease (AD) is a common neurodegenerative disease, neuroinflammation is an early pathological feature of AD. However, the alteration of the immune microenvironment in asymptomatic AD was not fully explained. In this study, we aimed to utilize the transcriptome data of AD patients in public databases to reveal the change of immune microenvironment in asymptomatic AD and screen the potential drug targets. A series of bioinformatics analyses were done, including differentially expressed genes (DEGs) screening, enrichment analysis, PPI network construction, and hub gene identification. Meanwhile, the selected hub genes were validated in APP/PS-1(AD) mice. Importantly, seven enrichment pathways and eight hub genes associated with inflammation were identified in asymptomatic AD. Correspondingly, more hub genes were increased in the hippocampus in AD mice compared to the other four brain regions. Accompanied by the activation of microglia and astrocytes, the inflammatory cytokines were increased in the hippocampus of AD mice. Subsequently, the relationship between HLA-C and inflammation was evaluated in AD mice. HLA-C was correlated with the activation of microglia, and HLA-DRB1 with IL-6 in the hippocampus. Moreover, HLA-C is expressed in the microglia cells and astrocytes. Further, five FDA-approved drugs (Itrazole, Dfo, Syrosingopine, Cefoperazone, and Pradaxa) were predicted as the common drug targeting HLA-C and HLA-DRB1 by molecular docking. Taken together, the results revealed the changes in the immune microenvironment of asymptomatic AD and provided a new perspective for the development of anti-inflammatory drugs for AD early treatment.
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Affiliation(s)
- Yingwei Zheng
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou 221004, PR China
| | - Xiaobo Yu
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, Shaanxi Normal University, Xi'an 710062, PR China
| | - Wenwen Li
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou 221004, PR China
| | - Fan Wu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou 221004, PR China
| | - Yunlu Gu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou 221004, PR China
| | - Keyao Liu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou 221004, PR China
| | - Sijue Tao
- Laboratory Animal Center, Zhejiang University, Hangzhou 310058, PR China
| | - Yue Liu
- Department of Radiation Biology, Faculty of Preventive Medicine, Fourth Military Medical University, Xi'an 710032, PR China; Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Fourth Military Medical University, Xi'an 710032, PR China.
| | - Qian Wang
- Department of Radiology, Xuzhou Central Hospital, Xuzhou 221009, PR China.
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2
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Fan X, Chen H, He W, Zhang J. Emerging microglial biology highlights potential therapeutic targets for Alzheimer's disease. Ageing Res Rev 2024; 101:102471. [PMID: 39218078 DOI: 10.1016/j.arr.2024.102471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/21/2024] [Accepted: 08/24/2024] [Indexed: 09/04/2024]
Abstract
Alzheimer's disease is a chronic degenerative disease of the central nervous system, which primarily affects elderly people and accounts for 70-80 % of dementia cases. The current prevailing amyloid cascade hypothesis suggests that Alzheimer's disease begins with the deposition of amyloid β (Aβ) in the brain. Major therapeutic strategies target Aβ production, aggregation, and clearance, although many clinical trials have shown that these therapeutic strategies are not sufficient to completely improve cognitive deficits in AD patients. Recent genome-wide association studies have identified that multiple important regulators are the most significant genetic risk factors for Alzheimer's disease, especially in the innate immune pathways. These genetic risk factors suggest a critical role for microglia, highlighting their therapeutic potential in treating neurodegenerative diseases. In this review, we discuss how these recently documented AD risk genes affect microglial function and AD pathology and how they can be further targeted to regulate microglial states and slow AD progression, especially the highly anticipated APOE and TREM2 targets. We focused on recent findings that modulation of innate and adaptive neuroimmune microenvironment crosstalk reverses cognitive deficits in AD patients. We also considered novel strategies for microglia in AD patients.
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Affiliation(s)
- Xi Fan
- Department of Immunology, CAMS Key laboratory T cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing 100005, China; Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Hui Chen
- Department of Immunology, CAMS Key laboratory T cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing 100005, China.
| | - Wei He
- Department of Immunology, CAMS Key laboratory T cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing 100005, China.
| | - Jianmin Zhang
- Department of Immunology, CAMS Key laboratory T cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing 100005, China; Changzhou Xitaihu Institute for Frontier Technology of Cell Therapy, Changzhou, Jiangsu 213000, China.
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Netzahualcoyotzi C, Santillán-Cigales JJ, Adalid-Peralta LV, Velasco I. Infiltration of immune cells to the brain and its relation to the pathogenesis of Alzheimer's and Parkinson's diseases. J Neurochem 2024; 168:2316-2334. [PMID: 38549444 DOI: 10.1111/jnc.16106] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 02/22/2024] [Accepted: 03/13/2024] [Indexed: 10/04/2024]
Abstract
The neurovascular unit, composed of vascular endothelium, vascular smooth muscle, extracellular matrix components, pericytes, astrocytes, microglia, and neurons, allows the highly regulated exchange of molecules and the limited trafficking of cells to the brain through coordinated signaling activity. The passage of peripheral immune cells to the brain parenchyma is observed when there is clear damage to the barriers of this neurovascular unit, as occurs in traumatic brain injury. The possibility of leukocyte infiltration to the brain in neurodegenerative conditions has been proposed. In this review, we focus on describing the evidence for peripheral immune cell infiltration to the brain in the two most frequent neurodegenerative diseases: Alzheimer's and Parkinson's diseases. In particular, we address the mechanisms that promote the passage of these cells into the brain under such pathological conditions. We also discuss the relevance of the resulting cellular interactions, which provide evidence that the presence of peripheral immune cells in the brain is a key point in these neurodegenerative diseases.
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Affiliation(s)
- Citlalli Netzahualcoyotzi
- Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - Juan Jair Santillán-Cigales
- Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Laura Virginia Adalid-Peralta
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - Iván Velasco
- Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
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van Olst L, Kamermans A, Halters S, van der Pol SMA, Rodriguez E, Verberk IMW, Verberk SGS, Wessels DWR, Rodriguez-Mogeda C, Verhoeff J, Wouters D, Van den Bossche J, Garcia-Vallejo JJ, Lemstra AW, Witte ME, van der Flier WM, Teunissen CE, de Vries HE. Adaptive immune changes associate with clinical progression of Alzheimer's disease. Mol Neurodegener 2024; 19:38. [PMID: 38658964 PMCID: PMC11044380 DOI: 10.1186/s13024-024-00726-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 03/29/2024] [Indexed: 04/26/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. METHODS We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). RESULTS We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. CONCLUSIONS Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology.
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Affiliation(s)
- Lynn van Olst
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands.
- Amsterdam Neuroscience, Neuroinfection & -Inflammation, Amsterdam, the Netherlands.
- Present address: The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Alwin Kamermans
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neuroinfection & -Inflammation, Amsterdam, the Netherlands
| | - Sem Halters
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neuroinfection & -Inflammation, Amsterdam, the Netherlands
| | - Susanne M A van der Pol
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neuroinfection & -Inflammation, Amsterdam, the Netherlands
| | - Ernesto Rodriguez
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands
| | - Inge M W Verberk
- Amsterdam Neuroscience, Neuroinfection & -Inflammation, Amsterdam, the Netherlands
- Department of Laboratory Medicine, Neurochemistry Laboratory, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
| | - Sanne G S Verberk
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischemic Syndromes, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Danielle W R Wessels
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
| | - Carla Rodriguez-Mogeda
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neuroinfection & -Inflammation, Amsterdam, the Netherlands
| | - Jan Verhoeff
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, the Netherlands
| | - Dorine Wouters
- Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischemic Syndromes, Amsterdam, the Netherlands
| | - Jan Van den Bossche
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischemic Syndromes, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Juan J Garcia-Vallejo
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, the Netherlands
| | - Afina W Lemstra
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Department of Neurology, Amsterdam UMC Location VUmc, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Maarten E Witte
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neuroinfection & -Inflammation, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Inflammatory Diseases, Amsterdam, the Netherlands
| | - Wiesje M van der Flier
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Department of Neurology, Amsterdam UMC Location VUmc, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Department of Epidemiology & Data Science, Amsterdam UMC Location VUmc, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Charlotte E Teunissen
- Amsterdam Neuroscience, Neuroinfection & -Inflammation, Amsterdam, the Netherlands
- Department of Laboratory Medicine, Neurochemistry Laboratory, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
| | - Helga E de Vries
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences, Microcirculation, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurovascular Disorders, Amsterdam, the Netherlands
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Guan Y, Cao M, Wu X, Yan J, Hao Y, Zhang C. CD28 null T cells in aging and diseases: From biology to assessment and intervention. Int Immunopharmacol 2024; 131:111807. [PMID: 38471362 DOI: 10.1016/j.intimp.2024.111807] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/25/2024] [Accepted: 03/04/2024] [Indexed: 03/14/2024]
Abstract
CD28null T cells, an atypical subset characterized by the loss of CD28 costimulatory molecule expression, exhibit functional variants and progressively expand with age. Moreover, T cells with these phenotypes are found in both typical and atypical humoral immune responses. Consequently, they accumulate during infectious diseases, autoimmune disorders, cardiovascular conditions, and neurodegenerative ailments. To provide an in-depth review of the current knowledge regarding CD28null T cells, we specifically focus on their phenotypic and functional characteristics as well as their physiological roles in aging and diseases. While uncertainties regarding the clinical utility remains, we will review the following two crucial research perspectives to explore clinical translational applications of the research on this specific T cell subset: 1) addressing the potential utility of CD28null T cells as immunological markers for prognosis and adverse outcomes in both aging and disease, and 2) speculating on the potential of targeting CD28null T cells as an interventional strategy for preventing or delaying immune aging processes and disease progression.
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Affiliation(s)
- Yuqi Guan
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Ming Cao
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Xiaofen Wu
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Jinhua Yan
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Yi Hao
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Cuntai Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China.
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6
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Hartnell IJ, Woodhouse D, Jasper W, Mason L, Marwaha P, Graffeuil M, Lau LC, Norman JL, Chatelet DS, Buee L, Nicoll JAR, Blum D, Dorothee G, Boche D. Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology. Brain 2024; 147:590-606. [PMID: 37703311 PMCID: PMC10834257 DOI: 10.1093/brain/awad309] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 07/23/2023] [Accepted: 08/11/2023] [Indexed: 09/15/2023] Open
Abstract
Frontotemporal lobar degeneration with tau (FTLD-tau) is a group of tauopathies that underlie ∼50% of FTLD cases. Identification of genetic risk variants related to innate/adaptive immunity have highlighted a role for neuroinflammation and neuroimmune interactions in FTLD. Studies have shown microglial and astrocyte activation together with T cell infiltration in the brain of THY-Tau22 tauopathy mice. However, this remains to be confirmed in FTLD-tau patients. We conducted a detailed post-mortem study of FTLD-tau cases including 45 progressive supranuclear palsy with clinical frontotemporal dementia, 33 Pick's disease, 12 FTLD-MAPT and 52 control brains to characterize the link between phosphorylated tau (pTau) epitopes and the innate and adaptive immunity. Tau pathology was assessed in the cerebral cortex using antibodies directed against: Tau-2 (phosphorylated and unphosphorylated tau), AT8 (pSer202/pThr205), AT100 (pThr212/pSer214), CP13 (pSer202), PHF1 (pSer396/pSer404), pThr181 and pSer356. The immunophenotypes of microglia and astrocytes were assessed with phenotypic markers (Iba1, CD68, HLA-DR, CD64, CD32a, CD16 for microglia and GFAP, EAAT2, glutamine synthetase and ALDH1L1 for astrocytes). The adaptive immune response was explored via CD4+ and CD8+ T cell quantification and the neuroinflammatory environment was investigated via the expression of 30 inflammatory-related proteins using V-Plex Meso Scale Discovery. As expected, all pTau markers were increased in FTLD-tau cases compared to controls. pSer356 expression was greatest in FTLD-MAPT cases versus controls (P < 0.0001), whereas the expression of other markers was highest in Pick's disease. Progressive supranuclear palsy with frontotemporal dementia consistently had a lower pTau protein load compared to Pick's disease across tau epitopes. The only microglial marker increased in FTLD-tau was CD16 (P = 0.0292) and specifically in FTLD-MAPT cases (P = 0.0150). However, several associations were detected between pTau epitopes and microglia, supporting an interplay between them. GFAP expression was increased in FTLD-tau (P = 0.0345) with the highest expression in Pick's disease (P = 0.0019), while ALDH1L1 was unchanged. Markers of astrocyte glutamate cycling function were reduced in FTLD-tau (P = 0.0075; Pick's disease: P < 0.0400) implying astrocyte reactivity associated with a decreased glutamate cycling activity, which was further associated with pTau expression. Of the inflammatory proteins assessed in the brain, five chemokines were upregulated in Pick's disease cases (P < 0.0400), consistent with the recruitment of CD4+ (P = 0.0109) and CD8+ (P = 0.0014) T cells. Of note, the CD8+ T cell infiltration was associated with pTau epitopes and microglial and astrocytic markers. Our results highlight that FTLD-tau is associated with astrocyte reactivity, remarkably little activation of microglia, but involvement of adaptive immunity in the form of chemokine-driven recruitment of T lymphocytes.
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Affiliation(s)
- Iain J Hartnell
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Declan Woodhouse
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - William Jasper
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Luke Mason
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Pavan Marwaha
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Manon Graffeuil
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
| | - Laurie C Lau
- Clinical and Experimental Sciences, Faculty of Medicine, Sir Henry Wellcome Laboratories, University of Southampton, Southampton O16 6YD, UK
| | - Jeanette L Norman
- Histochemistry Research Unit, Clinical and Experimental Sciences, Faculty of Medicine University of Southampton, Southampton SO16 6YD, UK
| | - David S Chatelet
- Biomedical Imaging Unit, University Hospital Southampton NHS Trust, Southampton SO16 6YD, UK
| | - Luc Buee
- University of Lille, Inserm, CHU Lille, UMR-S1172—Lille Neurosciences and Cognition, Lille 59045, France
- Alzheimer and Tauopathies, LabEX DISTALZ, Lille 59000, France
| | - James A R Nicoll
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- Department of Cellular Pathology, University Hospital Southampton NHS Trust, Southampton SO16 6YD, UK
| | - David Blum
- University of Lille, Inserm, CHU Lille, UMR-S1172—Lille Neurosciences and Cognition, Lille 59045, France
- Alzheimer and Tauopathies, LabEX DISTALZ, Lille 59000, France
| | - Guillaume Dorothee
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Immune System and Neuroinflammation Laboratory, Hôpital Saint-Antoine, Paris 75012, France
| | - Delphine Boche
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK
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7
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Zhang Z, Duan Z, Cui Y. CD8 + T cells in brain injury and neurodegeneration. Front Cell Neurosci 2023; 17:1281763. [PMID: 38077952 PMCID: PMC10702747 DOI: 10.3389/fncel.2023.1281763] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 10/30/2023] [Indexed: 02/19/2024] Open
Abstract
The interaction between the peripheral immune system and the brain is increasingly being recognized as an important layer of neuroimmune regulation and plays vital roles in brain homeostasis as well as neurological disorders. As an important population of T-cell lymphocytes, the roles of CD8+ T cells in infectious diseases and tumor immunity have been well established. Recently, increasing number of complex functions of CD8+ T cells in brain disorders have been revealed. However, an advanced summary and discussion of the functions and mechanisms of CD8+ T cells in brain injury and neurodegeneration are still lacking. Here, we described the differentiation and function of CD8+ T cells, reviewed the involvement of CD8+ T cells in the regulation of brain injury including stroke and traumatic brain injury and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and discussed therapeutic prospects and future study goals. Understanding these processes will promote the investigation of T-cell immunity in brain disorders and provide new intervention strategies for the treatment of brain injury and neurodegeneration.
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Affiliation(s)
- Zhaolong Zhang
- Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Zhongying Duan
- Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, Qingdao, Shandong, China
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Yu Cui
- Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, Qingdao, Shandong, China
- Qingdao Medical College, Qingdao University, Qingdao, China
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8
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Feng Y, Fan J, Cheng Y, Dai Q, Ma S. Stress regulates Alzheimer's disease progression via selective enrichment of CD8 + T cells. Cell Rep 2023; 42:113313. [PMID: 37858461 DOI: 10.1016/j.celrep.2023.113313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 08/25/2023] [Accepted: 10/04/2023] [Indexed: 10/21/2023] Open
Abstract
This study investigates stress's impact on Alzheimer's disease (AD) using male APP/PS1 transgenic mice. Negative stressors (chronic social defeat, restraint) and positive hedonia (environmental enrichment, EE) were applied. Stress worsens AD pathology, while EE slows progression. Brain RNA sequencing reveals interleukin-6 (IL-6) and IL-10 as key stress-related AD regulators. Flow cytometry shows that the CD8+/CD4+ T cell ratio shifts in response to stress exposure and EE. Stress exposure increases CD8+/CD4+ ratio, opposite to EE. Depletion and enrichment of CD8+ T cells both accelerate AD, indicating immune intervention's negative impact. Stress management and balanced immunity may aid AD therapy, highlighting novel potential treatment.
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Affiliation(s)
- Yilin Feng
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China; Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen 518055, China
| | - Jiaqi Fan
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China; Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen 518055, China; Institute for Brain and Cognitive Sciences, Tsinghua University, Beijing 100084, China
| | - Yifan Cheng
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China; Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen 518055, China
| | - Qionghai Dai
- Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen 518055, China; Institute for Brain and Cognitive Sciences, Tsinghua University, Beijing 100084, China
| | - Shaohua Ma
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China; Tsinghua-Berkeley Shenzhen Institute (TBSI), Shenzhen 518055, China; Institute for Brain and Cognitive Sciences, Tsinghua University, Beijing 100084, China.
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9
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Jorfi M, Park J, Hall CK, Lin CCJ, Chen M, von Maydell D, Kruskop JM, Kang B, Choi Y, Prokopenko D, Irimia D, Kim DY, Tanzi RE. Infiltrating CD8 + T cells exacerbate Alzheimer's disease pathology in a 3D human neuroimmune axis model. Nat Neurosci 2023; 26:1489-1504. [PMID: 37620442 PMCID: PMC11184920 DOI: 10.1038/s41593-023-01415-3] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 07/18/2023] [Indexed: 08/26/2023]
Abstract
Brain infiltration of peripheral immune cells and their interactions with brain-resident cells may contribute to Alzheimer's disease (AD) pathology. To examine these interactions, in the present study we developed a three-dimensional human neuroimmune axis model comprising stem cell-derived neurons, astrocytes and microglia, together with peripheral immune cells. We observed an increase in the number of T cells (but not B cells) and monocytes selectively infiltrating into AD relative to control cultures. Infiltration of CD8+ T cells into AD cultures led to increased microglial activation, neuroinflammation and neurodegeneration. Using single-cell RNA-sequencing, we identified that infiltration of T cells into AD cultures led to induction of interferon-γ and neuroinflammatory pathways in glial cells. We found key roles for the C-X-C motif chemokine ligand 10 (CXCL10) and its receptor, CXCR3, in regulating T cell infiltration and neuronal damage in AD cultures. This human neuroimmune axis model is a useful tool to study the effects of peripheral immune cells in brain disease.
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Affiliation(s)
- Mehdi Jorfi
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Charlestown, MA, USA.
| | - Joseph Park
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Clare K Hall
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
| | - Chih-Chung Jerry Lin
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
| | - Meng Chen
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
| | - Djuna von Maydell
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
| | - Jane M Kruskop
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
| | - Byunghoon Kang
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
| | - Younjung Choi
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
| | - Dmitry Prokopenko
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Daniel Irimia
- Harvard Medical School, Boston, MA, USA
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Charlestown, MA, USA
- Shriners Burns Hospital, Boston, MA, USA
| | - Doo Yeon Kim
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
- Harvard Medical School, Boston, MA, USA.
| | - Rudolph E Tanzi
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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10
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Abstract
Alzheimer's disease (AD) is a debilitating age-related neurodegenerative condition. Unbiased genetic studies have implicated a central role for microglia, the resident innate immune cells of the central nervous system, in AD pathogenesis. On-going efforts are clarifying the biology underlying these associations and the microglial pathways that are dysfunctional in AD. Several genetic risk factors converge to decrease the function of activating microglial receptors and increase the function of inhibitory receptors, resulting in a seemingly dampened microglial phenotype in AD. Moreover, many of these microglial proteins that are genetically associated with AD appear to interact and share pathways or regulatory mechanisms, presenting several points of convergence that may be strategic targets for therapeutic intervention. Here, we review some of these studies and their implications for microglial participation in AD pathogenesis.
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11
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Liu C, Xu S, Liu Q, Chai H, Luo Y, Li S. Identification of immune cells infiltrating in hippocampus and key genes associated with Alzheimer's disease. BMC Med Genomics 2023; 16:53. [PMID: 36915078 PMCID: PMC10009990 DOI: 10.1186/s12920-023-01458-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 02/13/2023] [Indexed: 03/16/2023] Open
Abstract
Alzheimer's disease (AD) is the most prevalent cause of dementia and is primarily associated with memory impairment and cognitive decline, but the etiology of AD has not been elucidated. In recent years, evidence has shown that immune cells play critical roles in AD pathology. In the current study, we collected the transcriptomic data of the hippocampus from gene expression omnibus database, and investigated the effect of immune cell infiltration in the hippocampus on AD, and analyzed the key genes that influence the pathogenesis of AD patients. The results revealed that the relative abundance of immune cells in the hippocampus of AD patients was altered. Of all given 28 kinds of immune cells, monocytes were the important immune cell associated with AD. We identified 4 key genes associated with both AD and monocytes, including KDELR1, SPTAN1, CDC16 and RBBP6, and they differentially expressed in 5XFAD mice and WT mice. The logistic regression and random forest models based on the 4 key genes could effectively distinguish AD from healthy samples. Our research provided a new perspective on immunotherapy for AD patients.
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Affiliation(s)
- Chenming Liu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, 200092, China
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Sutong Xu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, 200092, China
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Qiulu Liu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, 200092, China
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Huazhen Chai
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, 200092, China
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Yuping Luo
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, 200092, China.
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
| | - Siguang Li
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, 200092, China.
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
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12
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Zhou S, Li Y, Zhang Z, Yuan Y. An insight into the TAM system in Alzheimer's disease. Int Immunopharmacol 2023; 116:109791. [PMID: 36738678 DOI: 10.1016/j.intimp.2023.109791] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/13/2023] [Accepted: 01/24/2023] [Indexed: 02/05/2023]
Abstract
The TAM receptors may help delay the progression of Alzheimer's disease (AD). AD is the most common neurodegenerative disease associated with human aging. The TAM receptors, derived from the first letter of its three constituents -Tyro3, Axl, and Mertk, are associated with immune responses, cellular differentiation and migration, and clearance of apoptotic cells and debris, with the two canonical ligands, Growth Arrest Specific 6 (Gas6) and ProS1. Several kinds of research have indicated the participation of the TAM system in AD pathology. Also, the TAMs regulate multiple features of microglia, the significant sensors of disorder in the central nervous system (CNS). In this review, we describe the biology of the TAM receptors and ligands in the CNS. Then, we discuss the relationship between the TAM system and AD, specially focusing on its functional expression in the microglia. Finally, we also summarize some agents that could interfere with the TAM signaling pathways and discuss potential difficulties and strategies for drug development.
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Affiliation(s)
- Shiqi Zhou
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Yanyan Li
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Zhao Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Yuhe Yuan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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13
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Biose IJ, Ismael S, Ouvrier B, White AL, Bix GJ. The Potential Role of Integrin Signaling in Memory and Cognitive Impairment. Biomolecules 2023; 13:biom13010108. [PMID: 36671492 PMCID: PMC9855855 DOI: 10.3390/biom13010108] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/29/2022] [Accepted: 01/02/2023] [Indexed: 01/06/2023] Open
Abstract
Dementia currently has no cure and, due to the increased prevalence and associated economic and personal burden of this condition, current research efforts for the development of potential therapies have intensified. Recently, targeting integrins as a strategy to ameliorate dementia and other forms of cognitive impairment has begun to gain traction. Integrins are major bidirectional signaling receptors in mammalian cells, mediating various physiological processes such as cell-cell interaction and cell adhesion, and are also known to bind to the extracellular matrix. In particular, integrins play a critical role in the synaptic transmission of signals, hence their potential contribution to memory formation and significance in cognitive impairment. In this review, we describe the physiological roles that integrins play in the blood-brain barrier (BBB) and in the formation of memories. We also provide a clear overview of how integrins are implicated in BBB disruption following cerebral pathology. Given that vascular contributions to cognitive impairment and dementia and Alzheimer's' disease are prominent forms of dementia that involve BBB disruption, as well as chronic inflammation, we present current approaches shown to improve dementia-like conditions with integrins as a central focus. We conclude that integrins are vital in memory formation and that their disruption could lead to various forms of cognitive impairment. While further research to understand the relationships between integrins and memory is needed, we propose that the translational relevance of research efforts in this area could be improved through the use of appropriately aged, comorbid, male and female animals.
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Affiliation(s)
- Ifechukwude Joachim Biose
- Clinical Neuroscience Research Center, Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Saifudeen Ismael
- Clinical Neuroscience Research Center, Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Blake Ouvrier
- Clinical Neuroscience Research Center, Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Tulane Brain Institute, Tulane University, New Orleans, LA 70112, USA
| | - Amanda Louise White
- Clinical Neuroscience Research Center, Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Tulane Brain Institute, Tulane University, New Orleans, LA 70112, USA
| | - Gregory Jaye Bix
- Clinical Neuroscience Research Center, Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
- School of Medicine, Tulane University, New Orleans, LA 70112, USA
- Department of Neurology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70122, USA
- Correspondence: ; Tel.: +1-504-988-3564
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14
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Han PC, Hamlett ED. T Lymphocytes in the Pathogenesis and Progression of Alzheimer's Disease: Pursuing Direct Neuropathological Evidence. Curr Alzheimer Res 2023; 20:453-458. [PMID: 37670715 DOI: 10.2174/1567205020666230904151011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 04/09/2023] [Accepted: 07/04/2023] [Indexed: 09/07/2023]
Abstract
Multiple studies have proposed important roles of T cells in the pathogenesis of Alzheimer's disease. Given the successful application of immune-based therapy for cancer and a variety of diseases, T cell-modifying therapy becomes an attractive way to develop new therapies for Alzheimer's disease and perhaps neurodegenerative diseases in general. However, most of these studies address peripheral T cell responses, while direct pathological evidence documenting T cell infiltration relative to Alzheimer's disease pathological markers (i.e., amyloid plaque and neurofibrillary tangle) is sparse and at best, very preliminary in both human subjects and relevant animal models. Here, we concisely summarize the available pathological data that directly corresponds to T cell infiltration, critically analyze the current knowledge gaps, and thoughtfully propose several key recommendations for future research.
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Affiliation(s)
- Peng Cheng Han
- Department of Pathology, Anatomy and Laboratory Medicine, West Virginia University, School of Medicine, Morgantown, WV 26501, USA
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, WV 26501, USA
| | - Eric Daniel Hamlett
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29401, USA
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15
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Pan AL, Audrain M, Sakakibara E, Joshi R, Zhu X, Wang Q, Wang M, Beckmann ND, Schadt EE, Gandy S, Zhang B, Ehrlich ME, Salton SR. Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females. Cells 2022; 11:3880. [PMID: 36497141 PMCID: PMC9737364 DOI: 10.3390/cells11233880] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/05/2022] Open
Abstract
Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer's disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity protein phosphatase 4 (DUSP4) [also known as mitogen-activated protein kinase (MAPK) phosphatase 2] as an important node. Importantly, DUSP4 gene expression, like that of VGF, is downregulated in postmortem Alzheimer's disease (AD) brains. We investigated the roles that this VGF/DUSP4 network plays in the development of learning behavior impairment and neuropathology in the 5xFAD amyloidopathy mouse model. We found reductions in DUSP4 expression in the hippocampi of male AD subjects, correlating with increased CDR scores, and in 4-month-old female and 12-18-month-old male 5xFAD hippocampi. Adeno-associated virus (AAV5)-mediated overexpression of DUSP4 in 5xFAD mouse dorsal hippocampi (dHc) rescued impaired Barnes maze performance in females but not in males, while amyloid loads were reduced in both females and males. Bulk RNA sequencing of the dHc from 5-month-old mice overexpressing DUSP4, and Ingenuity Pathway and Enrichr analyses of differentially expressed genes (DEGs), revealed that DUSP4 reduced gene expression in female 5xFAD mice in neuroinflammatory, interferon-gamma (IFNγ), programmed cell death protein-ligand 1/programmed cell death protein 1 (PD-L1/PD-1), and extracellular signal-regulated kinase (ERK)/MAPK pathways, via which DUSP4 may modulate AD phenotype with gender-specificity.
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Affiliation(s)
- Allen L. Pan
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Mickael Audrain
- Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Emmy Sakakibara
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Rajeev Joshi
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Xiaodong Zhu
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Qian Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Minghui Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Noam D. Beckmann
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Eric E. Schadt
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Sam Gandy
- Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Department of Psychiatry and Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Michelle E. Ehrlich
- Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Stephen R. Salton
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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16
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Sutter PA, Crocker SJ. Glia as antigen-presenting cells in the central nervous system. Curr Opin Neurobiol 2022; 77:102646. [PMID: 36371828 PMCID: PMC10183975 DOI: 10.1016/j.conb.2022.102646] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/22/2022] [Accepted: 10/06/2022] [Indexed: 11/11/2022]
Abstract
The contribution of the cells within the central nervous system (CNS) toward adaptive immune responses is emerging and incompletely understood. Recent findings indicate important functional interactions between T-cells and glial cells within the CNS that may contribute to disease and neuropathology through antigen presentation. Although glia are not classically considered antigen-presenting cell (APC) types, there is growing evidence indicating that glial antigen presentation plays an important role in several neurological diseases. This review discusses these findings which incriminate microglia, astrocytes, and oligodendrocyte lineage cells as CNS-resident APC types with implications for understanding disease.
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Affiliation(s)
- Pearl A Sutter
- Departments of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Stephen J Crocker
- Departments of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA.
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17
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Liu H, Xie Y, Wang X, Abboud MI, Ma C, Ge W, Schofield CJ. Exploring links between 2-oxoglutarate-dependent oxygenases and Alzheimer's disease. Alzheimers Dement 2022; 18:2637-2668. [PMID: 35852137 PMCID: PMC10083964 DOI: 10.1002/alz.12733] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/12/2022] [Accepted: 06/10/2022] [Indexed: 01/31/2023]
Abstract
Hypoxia, that is, an inadequate oxygen supply, is linked to neurodegeneration and patients with cardiovascular disease are prone to Alzheimer's disease (AD). 2-Oxoglutarate and ferrous iron-dependent oxygenases (2OGDD) play a key role in the regulation of oxygen homeostasis by acting as hypoxia sensors. 2OGDD also have roles in collagen biosynthesis, lipid metabolism, nucleic acid repair, and the regulation of transcription and translation. Many biological processes in which the >60 human 2OGDD are involved are altered in AD patient brains, raising the question as to whether 2OGDD are involved in the transition from normal aging to AD. Here we give an overview of human 2OGDD and critically discuss their potential roles in AD, highlighting possible relationships with synapse dysfunction/loss. 2OGDD may regulate neuronal/glial differentiation through enzyme activity-dependent mechanisms and modulation of their activity has potential to protect against synapse loss. Work linking 2OGDD and AD is at an early stage, especially from a therapeutic perspective; we suggest integrated pathology and in vitro discovery research to explore their roles in AD is merited. We hope to help enable long-term research on the roles of 2OGDD and, more generally, oxygen/hypoxia in AD. We also suggest shorter term empirically guided clinical studies concerning the exploration of 2OGDD/oxygen modulators to help maintain synaptic viability are of interest for AD treatment.
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Affiliation(s)
- Haotian Liu
- State Key Laboratory of Medical Molecular Biology & Department of ImmunologyInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Yong Xie
- State Key Laboratory of Medical Molecular Biology & Department of ImmunologyInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijingChina
- National Clinical Research Center for OrthopedicsSports Medicine & RehabilitationDepartment of OrthopedicsGeneral Hospital of Chinese PLABeijingChina
| | - Xia Wang
- State Key Laboratory of Medical Molecular Biology & Department of ImmunologyInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Martine I. Abboud
- The Chemistry Research LaboratoryDepartment of Chemistry and the Ineos Oxford Institute for Antimicrobial ResearchUniversity of OxfordOxfordUK
| | - Chao Ma
- Department of Human Anatomy, Histology and EmbryologyNeuroscience CenterNational Human Brain Bank for Development and FunctionInstitute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Wei Ge
- State Key Laboratory of Medical Molecular Biology & Department of ImmunologyInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijingChina
| | - Christopher J. Schofield
- The Chemistry Research LaboratoryDepartment of Chemistry and the Ineos Oxford Institute for Antimicrobial ResearchUniversity of OxfordOxfordUK
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18
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Princiotta Cariddi L, Mauri M, Cosentino M, Versino M, Marino F. Alzheimer's Disease: From Immune Homeostasis to Neuroinflammatory Condition. Int J Mol Sci 2022; 23:13008. [PMID: 36361799 PMCID: PMC9658357 DOI: 10.3390/ijms232113008] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 08/13/2023] Open
Abstract
Alzheimer's Disease is the most common cause in the world of progressive cognitive decline. Although many modifiable and non-modifiable risk factors have been proposed, in recent years, neuroinflammation has been hypothesized to be an important contributing factor of Alzheimer's Disease pathogenesis. Neuroinflammation can occur through the combined action of the Central Nervous System resident immune cells and adaptive peripheral immune system. In the past years, immunotherapies for neurodegenerative diseases have focused wrongly on targeting protein aggregates Aβ plaques and NFT treatment. The role of both innate and adaptive immune cells has not been fully clarified, but several data suggest that immune system dysregulation plays a key role in neuroinflammation. Recent studies have focused especially on the role of the adaptive immune system and have shown that inflammatory markers are characterized by increased CD4+ Teff cells' activities and reduced circulating CD4+ Treg cells. In this review, we discuss the key role of both innate and adaptive immune systems in the degeneration and regeneration mechanisms in the pathogenesis of Alzheimer's Disease, with a focus on how the crosstalk between these two systems is able to sustain brain homeostasis or shift it to a neurodegenerative condition.
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Affiliation(s)
- Lucia Princiotta Cariddi
- PhD Program in Clinical and Experimental Medicine and Medical Humanities, University of Insubria, 21100 Varese, Italy
- Neurology and Stroke Unit, ASST Sette Laghi Hospital, 21100 Varese, Italy
| | - Marco Mauri
- Neurology and Stroke Unit, ASST Sette Laghi Hospital, 21100 Varese, Italy
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Marco Cosentino
- Center of Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy
| | - Maurizio Versino
- Neurology and Stroke Unit, ASST Sette Laghi Hospital, 21100 Varese, Italy
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy
| | - Franca Marino
- Center of Research in Medical Pharmacology, University of Insubria, 21100 Varese, Italy
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19
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Mason HD, McGavern DB. How the immune system shapes neurodegenerative diseases. Trends Neurosci 2022; 45:733-748. [PMID: 36075783 PMCID: PMC9746609 DOI: 10.1016/j.tins.2022.08.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/10/2022] [Accepted: 08/01/2022] [Indexed: 12/15/2022]
Abstract
Neurodegenerative diseases are a major cause of death and disability worldwide and are influenced by many factors including age, genetics, and injuries. While these diseases are often thought to result from the accumulation and spread of aberrant proteins, recent studies have demonstrated that they can be shaped by the innate and adaptive immune system. Resident myeloid cells typically mount a sustained response to the degenerating CNS, but peripheral leukocytes such as T and B cells can also alter disease trajectories. Here, we review the sometimes-dichotomous roles played by immune cells during neurodegenerative diseases and explore how brain trauma can serve as a disease initiator or accelerant. We also offer insights into how failure to properly resolve a CNS injury might promote the development of a neurodegenerative disease.
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Affiliation(s)
- Hannah D Mason
- Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dorian B McGavern
- Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
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20
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Zieneldien T, Kim J, Sawmiller D, Cao C. The Immune System as a Therapeutic Target for Alzheimer’s Disease. Life (Basel) 2022; 12:life12091440. [PMID: 36143476 PMCID: PMC9506058 DOI: 10.3390/life12091440] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/11/2022] [Accepted: 09/14/2022] [Indexed: 11/25/2022] Open
Abstract
Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder and is the most common cause of dementia. Furthermore, aging is considered the most critical risk factor for AD. However, despite the vast amount of research and resources allocated to the understanding and development of AD treatments, setbacks have been more prominent than successes. Recent studies have shown that there is an intricate connection between the immune and central nervous systems, which can be imbalanced and thereby mediate neuroinflammation and AD. Thus, this review examines this connection and how it can be altered with AD. Recent developments in active and passive immunotherapy for AD are also discussed as well as suggestions for improving these therapies moving forward.
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Affiliation(s)
- Tarek Zieneldien
- Department of Pharmaceutical Science, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
| | - Janice Kim
- Department of Pharmaceutical Science, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
| | - Darrell Sawmiller
- MegaNano BioTech, Inc., 3802 Spectrum Blvd. Suite 122, Tampa, FL 33612, USA
| | - Chuanhai Cao
- Department of Pharmaceutical Science, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
- USF-Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FL 33613, USA
- Correspondence:
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21
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Chen Y, Colonna M. Spontaneous and induced adaptive immune responses in Alzheimer's disease: new insights into old observations. Curr Opin Immunol 2022; 77:102233. [PMID: 35839620 DOI: 10.1016/j.coi.2022.102233] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/28/2022] [Accepted: 06/06/2022] [Indexed: 01/20/2023]
Abstract
Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Although AD is primarily a neurological disorder distinguished by amyloid β plaques and intracellular neurofibrillary tangles, the immune system can impact the progression of the disease and may be targeted for therapeutic purposes. To date, most studies have focused on innate immune responses of microglia. However, emerging evidence implicates adaptive immune responses by T cells and B cells in the progression of AD. Moreover, the recent approval of an antibody that promotes amyloid β plaque clearance for AD therapy has pinpointed adaptive immunity as a fertile ground for the design of novel therapeutic approaches. Here, we highlight key studies delineating T cell and B cell responses in human AD and mouse models of AD, identify open questions on the specificity, development and impact of these responses and discuss outlooks for future studies and novel therapeutic avenues.
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Affiliation(s)
- Yun Chen
- Department of Pathology and Immunology and Department of Neurology, Washington University School of Medicine in St Louis, USA
| | - Marco Colonna
- Department of Pathology and Immunology and Department of Neurology, Washington University School of Medicine in St Louis, USA.
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22
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Stahr N, Galkina EV. Immune Response at the Crossroads of Atherosclerosis and Alzheimer's Disease. Front Cardiovasc Med 2022; 9:870144. [PMID: 35872901 PMCID: PMC9298512 DOI: 10.3389/fcvm.2022.870144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 06/02/2022] [Indexed: 11/30/2022] Open
Abstract
Alzheimer's disease (AD) and cardiovascular disease (CVD) are pathologies that are characterized by common signatures of vascular dysfunction and chronic inflammation that are accelerated with aging. Importantly, epidemiological studies report an independent interaction between AD and CVD and data suggest that chronic inflammation in CVD may accelerate AD development. Atherosclerosis affects most large to medium sized arteries including those supplying the cerebral circulation. Vascular dysfunction caused by atherosclerosis results in blood brain barrier breakdown, inflammation, an impaired clearance of amyloid-beta (Aβ), and finally ends with neurovascular dysfunction. Numerous data indicate that innate and adaptive immune responses shape atherogenesis and increasing evidence suggests an implication of the immune response in AD progression. Currently, mechanisms by which these two diseases are interconnected with each other are not well-defined. In this review, we discuss the recent advances in our understanding of the intertwined role of the immune response in atherosclerosis and AD and the implications of these findings for human health.
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23
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van Olst L, Coenen L, Nieuwland JM, Rodriguez-Mogeda C, de Wit NM, Kamermans A, Middeldorp J, de Vries HE. Crossing borders in Alzheimer's disease: A T cell's perspective. Adv Drug Deliv Rev 2022; 188:114398. [PMID: 35780907 DOI: 10.1016/j.addr.2022.114398] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is the most common form of dementia affecting millions of people worldwide. While different immunotherapies are imminent, currently only disease-modifying medications are available and a cure is lacking. Over the past decade, immunological interfaces of the central nervous system (CNS) and their role in neurodegenerative diseases received increasing attention. Specifically, emerging evidence shows that subsets of circulating CD8+ T cells cross the brain barriers and associate with AD pathology. To gain more insight into how the adaptive immune system is involved in disease pathogenesis, we here provide a comprehensive overview of the contribution of T cells to AD pathology, incorporating changes at the brain barriers. In addition, we review studies that provide translation of these findings by targeting T cells to combat AD pathology and cognitive decline. Importantly, these data show that immunological changes in AD are not confined to the CNS and that AD-associated systemic immune changes appear to affect brain homeostasis.
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Affiliation(s)
- L van Olst
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - L Coenen
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands; Department of Neurobiology and Aging, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - J M Nieuwland
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands; Department of Neurobiology and Aging, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - C Rodriguez-Mogeda
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - N M de Wit
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - A Kamermans
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - J Middeldorp
- Department of Neurobiology and Aging, Biomedical Primate Research Centre, Rijswijk, The Netherlands
| | - H E de Vries
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.
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24
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Lima MN, Barbosa-Silva MC, Maron-Gutierrez T. Microglial Priming in Infections and Its Risk to Neurodegenerative Diseases. Front Cell Neurosci 2022; 16:878987. [PMID: 35783096 PMCID: PMC9240317 DOI: 10.3389/fncel.2022.878987] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/26/2022] [Indexed: 11/29/2022] Open
Abstract
Infectious diseases of different etiologies have been associated with acute and long-term neurological consequences. The primary cause of these consequences appears to be an inflammatory process characterized primarily by a pro-inflammatory microglial state. Microglial cells, the local effectors' cells of innate immunity, once faced by a stimulus, alter their morphology, and become a primary source of inflammatory cytokines that increase the inflammatory process of the brain. This inflammatory scenario exerts a critical role in the pathogenesis of neurodegenerative diseases. In recent years, several studies have shown the involvement of the microglial inflammatory response caused by infections in the development of neurodegenerative diseases. This has been associated with a transitory microglial state subsequent to an inflammatory response, known as microglial priming, in which these cells are more responsive to stimuli. Thus, systemic inflammation and infections induce a transitory state in microglia that may lead to changes in their state and function, making priming them for subsequent immune challenges. However, considering that microglia are long-lived cells and are repeatedly exposed to infections during a lifetime, microglial priming may not be beneficial. In this review, we discuss the relationship between infections and neurodegenerative diseases and how this may rely on microglial priming.
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Affiliation(s)
- Maiara N. Lima
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Fiocruz, Rio de Janeiro, Brazil
| | - Maria C. Barbosa-Silva
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Fiocruz, Rio de Janeiro, Brazil
| | - Tatiana Maron-Gutierrez
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Fiocruz, Rio de Janeiro, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation, Rio de Janeiro, Brazil
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25
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Hashioka S, Inoue K, Otsuki K, Hayashida M, Wake R, Kawano N, Takeshita H, Inagaki M. Contribution of “Genuine Microglia” to Alzheimer's Disease Pathology. Front Aging Neurosci 2022; 14:815307. [PMID: 35401156 PMCID: PMC8989142 DOI: 10.3389/fnagi.2022.815307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 03/03/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Sadayuki Hashioka
- Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan
- *Correspondence: Sadayuki Hashioka
| | - Ken Inoue
- Medical Sciences Cluster, Health Service Center, Research and Education Faculty, Kochi University, Kochi, Japan
| | - Koji Otsuki
- Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Maiko Hayashida
- Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Rei Wake
- Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Noriyuki Kawano
- The Center for Peace, Hiroshima University, Hiroshima, Japan
| | - Haruo Takeshita
- Department of Legal Medicine, Faculty of Medicine, Shimane University, Izumo, Japan
| | - Masatoshi Inagaki
- Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan
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26
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Womack TR, Vollert CT, Ohia-Nwoko O, Schmitt M, Montazari S, Beckett TL, Mayerich D, Murphy MP, Eriksen JL. Prostacyclin Promotes Degenerative Pathology in a Model of Alzheimer's Disease. Front Cell Neurosci 2022; 16:769347. [PMID: 35197825 PMCID: PMC8860182 DOI: 10.3389/fncel.2022.769347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 01/07/2022] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the most common form of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression significantly worsened multiple measures associated with amyloid-β (Aβ) disease pathologies. Mice overexpressing both Aβ and PGI2 exhibited impaired learning and memory and increased anxiety-like behavior compared with non-transgenic and PGI2 control mice. PGI2 overexpression accelerated the development of Aβ accumulation in the brain and selectively increased the production of soluble Aβ42. PGI2 damaged the microvasculature through alterations in vascular length and branching; Aβ expression exacerbated these effects. Our findings demonstrate that chronic prostacyclin expression plays a novel and unexpected role that hastens the development of the AD phenotype.
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Affiliation(s)
- Tasha R. Womack
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, United States
| | - Craig T. Vollert
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, United States
| | - Odochi Ohia-Nwoko
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, United States
| | - Monika Schmitt
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, United States
| | - Saghi Montazari
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, United States
| | - Tina L. Beckett
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, United States
| | - David Mayerich
- Department of Electrical and Computer Engineering, University of Houston, Houston, TX, United States
| | - Michael Paul Murphy
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, United States
| | - Jason L. Eriksen
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, United States
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27
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Rickenbach C, Gericke C. Specificity of Adaptive Immune Responses in Central Nervous System Health, Aging and Diseases. Front Neurosci 2022; 15:806260. [PMID: 35126045 PMCID: PMC8812614 DOI: 10.3389/fnins.2021.806260] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 12/29/2021] [Indexed: 12/25/2022] Open
Abstract
The field of neuroimmunology endorses the involvement of the adaptive immune system in central nervous system (CNS) health, disease, and aging. While immune cell trafficking into the CNS is highly regulated, small numbers of antigen-experienced lymphocytes can still enter the cerebrospinal fluid (CSF)-filled compartments for regular immune surveillance under homeostatic conditions. Meningeal lymphatics facilitate drainage of brain-derived antigens from the CSF to deep cervical lymph nodes to prime potential adaptive immune responses. During aging and CNS disorders, brain barriers and meningeal lymphatic functions are impaired, and immune cell trafficking and antigen efflux are altered. In this context, alterations in the immune cell repertoire of blood and CSF and T and B cells primed against CNS-derived autoantigens have been observed in various CNS disorders. However, for many diseases, a causal relationship between observed immune responses and neuropathological findings is lacking. Here, we review recent discoveries about the association between the adaptive immune system and CNS disorders such as autoimmune neuroinflammatory and neurodegenerative diseases. We focus on the current challenges in identifying specific T cell epitopes in CNS diseases and discuss the potential implications for future diagnostic and treatment options.
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Affiliation(s)
- Chiara Rickenbach
- Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland
| | - Christoph Gericke
- Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland
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28
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Joshi C, Sivaprakasam K, Christley S, Ireland S, Rivas J, Zhang W, Sader D, Logan R, Lambracht-Washington D, Rosenberg R, Cullum M, Hitt B, Li QZ, Barber R, Greenberg B, Cowell L, Zhang R, Stowe A, Huebinger R, Kelley B, Monson N. CSF-Derived CD4 + T-Cell Diversity Is Reduced in Patients With Alzheimer Clinical Syndrome. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2022; 9:e1106. [PMID: 34848502 PMCID: PMC8631792 DOI: 10.1212/nxi.0000000000001106] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 09/14/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND OBJECTIVES Patients with Alzheimer dementia display evidence of amyloid-related neurodegeneration. Our focus was to determine whether such patients also display evidence of a disease-targeting adaptive immune response mediated by CD4+ T cells. To test this hypothesis, we evaluated the CSF immune profiles of patients with Alzheimer clinical syndrome (ACS), who display clinically defined dementia. METHODS Innate and adaptive immune profiles of patients with ACS were measured using multicolor flow cytometry. CSF-derived CD4+ and CD8+ T-cell receptor repertoire genetics were measured using next-generation sequencing. Brain-specific autoantibody signatures of CSF-derived antibody pools were measured using array technology or ELISA. CSF from similar-age healthy controls (HCs) was used as a comparator cohort. RESULTS Innate cells were expanded in the CSF of patients with ACS in comparison to HCs, and innate cell expansion increased with age in the patients with ACS, but not HCs. Despite innate cell expansion in the CSF, the frequency of total CD4+ T cells reduced with age in the patients with ACS. T-cell receptor repertoire genetics indicated that T-cell clonal expansion is enhanced, and diversity is reduced in the patients with ACS compared with similar-age HCs. DISCUSSION Examination of CSF indicates that CD4+ T cell-mediated adaptive immune responses are altered in patients with ACS. Understanding the underlying mechanisms affecting adaptive immunity will help move us toward the goal of slowing cognitive decline.
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Affiliation(s)
- Chaitanya Joshi
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Karthigayini Sivaprakasam
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Scott Christley
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Sara Ireland
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Jacqueline Rivas
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Wei Zhang
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Danielle Sader
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Rebecca Logan
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Doris Lambracht-Washington
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Roger Rosenberg
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Munro Cullum
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Brian Hitt
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Quan-Zhen Li
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Robert Barber
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Benjamin Greenberg
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Lindsay Cowell
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Rong Zhang
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Ann Stowe
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Ryan Huebinger
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Brendan Kelley
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
| | - Nancy Monson
- From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY
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29
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Neuroimmune contributions to Alzheimer's disease: a focus on human data. Mol Psychiatry 2022; 27:3164-3181. [PMID: 35668160 PMCID: PMC9168642 DOI: 10.1038/s41380-022-01637-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 05/05/2022] [Accepted: 05/18/2022] [Indexed: 12/12/2022]
Abstract
The past decade has seen the convergence of a series of new insights that arose from genetic and systems analyses of Alzheimer's disease (AD) with a wealth of epidemiological data from a variety of fields; this resulted in renewed interest in immune responses as important, potentially causal components of AD. Here, we focus primarily on a review of human data which has recently yielded a set of robust, reproducible results that exist in a much larger universe of conflicting reports stemming from small studies with important limitations in their study design. Thus, we are at an important crossroads in efforts to first understand at which step of the long, multiphasic course of AD a given immune response may play a causal role and then modulate this response to slow or block the pathophysiology of AD. We have a wealth of new experimental tools, analysis methods, and capacity to sample human participants at large scale longitudinally; these resources, when coupled to a foundation of reproducible results and novel study designs, will enable us to monitor human immune function in the CNS at the level of complexity that is required while simultaneously capturing the state of the peripheral immune system. This integration of peripheral and central perturbations in immune responses results in pathologic responses in the central nervous system parenchyma where specialized cellular microenvironments composed of multiple cell subtypes respond to these immune perturbations as well as to environmental exposures, comorbidities and the impact of the advancing life course. Here, we offer an overview that seeks to illustrate the large number of interconnecting factors that ultimately yield the neuroimmune component of AD.
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30
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Brod SA. Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer's Disease. J Alzheimers Dis 2021; 85:457-472. [PMID: 34842189 DOI: 10.3233/jad-215125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Systemic inflammation is an organism's response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer's disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the "principal culprit" in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.
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Affiliation(s)
- Staley A Brod
- Department of Neurology, Medical College of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA
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31
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Bettcher BM, Tansey MG, Dorothée G, Heneka MT. Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus. Nat Rev Neurol 2021; 17:689-701. [PMID: 34522039 PMCID: PMC8439173 DOI: 10.1038/s41582-021-00549-x] [Citation(s) in RCA: 238] [Impact Index Per Article: 59.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2021] [Indexed: 02/08/2023]
Abstract
Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates pathological alterations in central and peripheral immune responses that change over time. Considering AD as a systemic immune process raises important questions about how communication between the peripheral and central compartments occurs and whether this crosstalk represents a therapeutic target. We established a whitepaper workgroup to delineate the current status of the field and to outline a research prospectus for advancing our understanding of peripheral-central immune crosstalk in AD. To guide the prospectus, we begin with an overview of seminal clinical observations that suggest a role for peripheral immune dysregulation and peripheral-central immune communication in AD, followed by formative animal data that provide insights into possible mechanisms for these clinical findings. We then present a roadmap that defines important next steps needed to overcome conceptual and methodological challenges, opportunities for future interdisciplinary research, and suggestions for translating promising mechanistic studies into therapeutic interventions.
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Affiliation(s)
- Brianne M Bettcher
- Behavioral Neurology Section, Department of Neurology, University of Colorado Alzheimer's and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| | - Malú G Tansey
- Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA
| | - Guillaume Dorothée
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, Team "Immune System and Neuroinflammation", Hôpital Saint-Antoine, Paris, France
| | - Michael T Heneka
- Department of Neurodegenerative Diseases & Geropsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany
- Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
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32
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El Idrissi F, Gressier B, Devos D, Belarbi K. A Computational Exploration of the Molecular Network Associated to Neuroinflammation in Alzheimer's Disease. Front Pharmacol 2021; 12:630003. [PMID: 34335238 PMCID: PMC8319636 DOI: 10.3389/fphar.2021.630003] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 06/29/2021] [Indexed: 12/13/2022] Open
Abstract
Neuroinflammation, as defined by the presence of classically activated microglia, is thought to play a key role in numerous neurodegenerative disorders such as Alzheimer’s disease. While modulating neuroinflammation could prove beneficial against neurodegeneration, identifying its most relevant biological processes and pharmacological targets remains highly challenging. In the present study, we combined text-mining, functional enrichment and protein-level functional interaction analyses to 1) identify the proteins significantly associated to neuroinflammation in Alzheimer’s disease over the scientific literature, 2) distinguish the key proteins most likely to control the neuroinflammatory processes significantly associated to Alzheimer's disease, 3) identify their regulatory microRNAs among those dysregulated in Alzheimer's disease and 4) assess their pharmacological targetability. 94 proteins were found to be significantly associated to neuroinflammation in Alzheimer’s disease over the scientific literature and IL4, IL10 and IL13 signaling as well as TLR-mediated MyD88- and TRAF6-dependent responses were their most significantly enriched biological processes. IL10, TLR4, IL6, AKT1, CRP, IL4, CXCL8, TNF-alpha, ITGAM, CCL2 and NOS3 were identified as the most potent regulators of the functional interaction network formed by these immune processes. These key proteins were indexed to be regulated by 63 microRNAs dysregulated in Alzheimer's disease, 13 long non-coding RNAs and targetable by 55 small molecules and 8 protein-based therapeutics. In conclusion, our study identifies eleven key proteins with the highest ability to control neuroinflammatory processes significantly associated to Alzheimer’s disease, as well as pharmacological compounds with single or pleiotropic actions acting on them. As such, it may facilitate the prioritization of diagnostic and target-engagement biomarkers as well as the development of effective therapeutic strategies against neuroinflammation in Alzheimer’s disease.
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Affiliation(s)
- Fatima El Idrissi
- Univ. Lille, Inserm, CHU-Lille, Lille Neuroscience & Cognition, Lille, France.,Département de Pharmacologie de la Faculté de Pharmacie, Univ. Lille, Lille, France
| | - Bernard Gressier
- Univ. Lille, Inserm, CHU-Lille, Lille Neuroscience & Cognition, Lille, France.,Département de Pharmacologie de la Faculté de Pharmacie, Univ. Lille, Lille, France
| | - David Devos
- Univ. Lille, Inserm, CHU-Lille, Lille Neuroscience & Cognition, Lille, France.,Département de Pharmacologie Médicale, I-SITE ULNE, LiCEND, Lille, France
| | - Karim Belarbi
- Univ. Lille, Inserm, CHU-Lille, Lille Neuroscience & Cognition, Lille, France.,Département de Pharmacologie de la Faculté de Pharmacie, Univ. Lille, Lille, France
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33
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Ojo JO, Reed JM, Crynen G, Vallabhaneni P, Evans J, Shackleton B, Eisenbaum M, Ringland C, Edsell A, Mullan M, Crawford F, Bachmeier C. Molecular Pathobiology of the Cerebrovasculature in Aging and in Alzheimers Disease Cases With Cerebral Amyloid Angiopathy. Front Aging Neurosci 2021; 13:658605. [PMID: 34079449 PMCID: PMC8166206 DOI: 10.3389/fnagi.2021.658605] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Cerebrovascular dysfunction and cerebral amyloid angiopathy (CAA) are hallmark features of Alzheimer's disease (AD). Molecular damage to cerebrovessels in AD may result in alterations in vascular clearance mechanisms leading to amyloid deposition around blood vessels and diminished neurovascular-coupling. The sequelae of molecular events leading to these early pathogenic changes remains elusive. To address this, we conducted a comprehensive in-depth molecular characterization of the proteomic changes in enriched cerebrovessel fractions isolated from the inferior frontal gyrus of autopsy AD cases with low (85.5 ± 2.9 yrs) vs. high (81 ± 4.4 yrs) CAA score, aged-matched control (87.4 ± 1.5 yrs) and young healthy control (47 ± 3.3 yrs) cases. We employed a 10-plex tandem isobaric mass tag approach in combination with our ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method. Enriched cerebrovascular fractions showed very high expression levels of proteins specific to endothelial cells, mural cells (pericytes and smooth muscle cells), and astrocytes. We observed 150 significantly regulated proteins in young vs. aged control cerebrovessels. The top pathways significantly modulated with aging included chemokine, reelin, HIF1α and synaptogenesis signaling pathways. There were 213 proteins significantly regulated in aged-matched control vs. high CAA cerebrovessels. The top three pathways significantly altered from this comparison were oxidative phosphorylation, Sirtuin signaling pathway and TCA cycle II. Comparison between low vs. high CAA cerebrovessels identified 84 significantly regulated proteins. Top three pathways significantly altered between low vs. high CAA cerebrovessels included TCA Cycle II, Oxidative phosphorylation and mitochondrial dysfunction. Notably, high CAA cases included more advanced AD pathology thus cerebrovascular effects may be driven by the severity of amyloid and Tangle pathology. These descriptive proteomic changes provide novel insights to explain the age-related and AD-related cerebrovascular changes contributing to AD pathogenesis. Particularly, disturbances in energy bioenergetics and mitochondrial biology rank among the top AD pathways altered in cerebrovessels. Targeting these failed mechanisms in endothelia and mural cells may provide novel disease modifying targets for developing therapeutic strategies against cerebrovascular deterioration and promoting cerebral perfusion in AD. Our future work will focus on interrogating and validating these novel targets and pathways and their functional significance.
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Affiliation(s)
- Joseph O. Ojo
- Roskamp Institute, Sarasota, FL, United States
- James A. Haley Veterans' Hospital, Tampa, FL, United States
- The Open University, Milton Keynes, United Kingdom
| | - Jon M. Reed
- Roskamp Institute, Sarasota, FL, United States
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States
| | | | | | - James Evans
- Roskamp Institute, Sarasota, FL, United States
| | - Benjamin Shackleton
- Roskamp Institute, Sarasota, FL, United States
- The Open University, Milton Keynes, United Kingdom
| | - Maximillian Eisenbaum
- Roskamp Institute, Sarasota, FL, United States
- The Open University, Milton Keynes, United Kingdom
| | - Charis Ringland
- Roskamp Institute, Sarasota, FL, United States
- The Open University, Milton Keynes, United Kingdom
| | | | - Michael Mullan
- Roskamp Institute, Sarasota, FL, United States
- The Open University, Milton Keynes, United Kingdom
| | - Fiona Crawford
- Roskamp Institute, Sarasota, FL, United States
- James A. Haley Veterans' Hospital, Tampa, FL, United States
- The Open University, Milton Keynes, United Kingdom
| | - Corbin Bachmeier
- Roskamp Institute, Sarasota, FL, United States
- The Open University, Milton Keynes, United Kingdom
- Bay Pines VA Healthcare System, Bay Pines, FL, United States
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34
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Hendrickx JO, Martinet W, Van Dam D, De Meyer GRY. Inflammation, Nitro-Oxidative Stress, Impaired Autophagy, and Insulin Resistance as a Mechanistic Convergence Between Arterial Stiffness and Alzheimer's Disease. Front Mol Biosci 2021; 8:651215. [PMID: 33855048 PMCID: PMC8039307 DOI: 10.3389/fmolb.2021.651215] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/03/2021] [Indexed: 12/12/2022] Open
Abstract
The average age of the world's elderly population is steadily increasing. This unprecedented rise in the aged world population will increase the prevalence of age-related disorders such as cardiovascular disease (CVD) and neurodegeneration. In recent years, there has been an increased interest in the potential interplay between CVDs and neurodegenerative syndromes, as several vascular risk factors have been associated with Alzheimer's disease (AD). Along these lines, arterial stiffness is an independent risk factor for both CVD and AD. In this review, we discuss several inflammaging-related disease mechanisms including acute tissue-specific inflammation, nitro-oxidative stress, impaired autophagy, and insulin resistance which may contribute to the proposed synergism between arterial stiffness and AD.
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Affiliation(s)
- Jhana O. Hendrickx
- Laboratory of Physiopharmacology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Wim Martinet
- Laboratory of Physiopharmacology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Debby Van Dam
- Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
- Department of Neurology and Alzheimer Research Center, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - Guido R. Y. De Meyer
- Laboratory of Physiopharmacology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium
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35
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Batterman KV, Cabrera PE, Moore TL, Rosene DL. T Cells Actively Infiltrate the White Matter of the Aging Monkey Brain in Relation to Increased Microglial Reactivity and Cognitive Decline. Front Immunol 2021; 12:607691. [PMID: 33664743 PMCID: PMC7920950 DOI: 10.3389/fimmu.2021.607691] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 01/25/2021] [Indexed: 02/06/2023] Open
Abstract
Normal aging is characterized by declines in processing speed, learning, memory, and executive function even in the absence of neurodegenerative diseases such as Alzheimer's Disease (AD). In normal aging monkeys and humans, neuronal loss does not account for cognitive impairment. Instead, loss of white matter volume and an accumulation of myelin sheath pathology begins in middle age and is associated with cognitive decline. It is unknown what causes this myelin pathology, but it likely involves increased neuroinflammation in white matter and failures in oligodendrocyte function (maturation and repair). In frontal white matter tracts vulnerable to myelin damage, microglia become chronically reactive and secrete harmful pro-inflammatory cytokines. Despite being in a phagocytic state, these microglia are ineffective at phagocytosing accruing myelin debris, which directly inhibits myelin sheath repair. Here, we asked whether reported age-related increases in pro-inflammatory markers were accompanied by an adaptive immune response involving T cells. We quantified T cells with immunohistochemistry in the brains of 34 cognitively characterized monkeys and found an age-related increase in perivascular T cells that surround CNS vasculature. We found a surprising age-related increase in T cells that infiltrate the white matter parenchyma. In the cingulum bundle the percentage of these parenchymal T cells increased with age relative to those in the perivascular space. In contrast, infiltrating T cells were rarely found in surrounding gray matter regions. We assessed whether T cell infiltration correlated with fibrinogen extravasation from the vasculature as a measure of BBB leakiness and found no correlation, suggesting that T cell infiltration is not a result of passive extravasation. Importantly, the density of T cells in the cingulum bundle correlated with microglial reactivity and with cognitive impairment. This is the first demonstration that T cell infiltration of white matter is associated with cognitive decline in the normal aging monkey.
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Affiliation(s)
- Katelyn V Batterman
- Laboratory for Cognitive Neurobiology, Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, United States
| | - Payton E Cabrera
- Laboratory for Cognitive Neurobiology, Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, United States
| | - Tara L Moore
- Laboratory for Cognitive Neurobiology, Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, United States.,Laboratory of Interventions for Cortical Injury and Cognitive Decline, Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, United States.,Center for Systems Neuroscience, Boston University, Boston, MA, United States
| | - Douglas L Rosene
- Laboratory for Cognitive Neurobiology, Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, United States.,Center for Systems Neuroscience, Boston University, Boston, MA, United States
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36
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Engin AB, Engin A. Alzheimer's Disease and Protein Kinases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1275:285-321. [PMID: 33539020 DOI: 10.1007/978-3-030-49844-3_11] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder and accounts for more than 60-80% of all cases of dementia. Loss of pyramidal neurons, extracellular amyloid beta (Abeta) accumulated senile plaques, and neurofibrillary tangles that contain hyperphosphorylated tau constitute the main pathological alterations in AD.Synaptic dysfunction and extrasynaptic N-methyl-D-aspartate receptor (NMDAR) hyperactivation contributes to excitotoxicity in patients with AD. Amyloid precursor protein (APP) and Abeta promoted neurodegeneration develop through the activation of protein kinase signaling cascade in AD. Furthermore, ultimate neuronal death in AD is under control of protein kinases-related signaling pathways. In this chapter, critical check-points within the cross-talk between neuron and protein kinases have been defined regarding the initiation and progression of AD. In this context, amyloid cascade hypothesis, neuroinflammation, oxidative stress, granulovacuolar degeneration, loss of Wnt signaling, Abeta-related synaptic alterations, prolonged calcium ions overload and NMDAR-related synaptotoxicity, damage signals hypothesis and type-3 diabetes are discussed briefly.In addition to clinical perspective of AD pathology, recommendations that might be effective in the treatment of AD patients have been reviewed.
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Affiliation(s)
- Ayse Basak Engin
- Department of Toxicology, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
| | - Atilla Engin
- Department of General Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey
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37
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Stojić-Vukanić Z, Hadžibegović S, Nicole O, Nacka-Aleksić M, Leštarević S, Leposavić G. CD8+ T Cell-Mediated Mechanisms Contribute to the Progression of Neurocognitive Impairment in Both Multiple Sclerosis and Alzheimer's Disease? Front Immunol 2020; 11:566225. [PMID: 33329528 PMCID: PMC7710704 DOI: 10.3389/fimmu.2020.566225] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 08/17/2020] [Indexed: 12/20/2022] Open
Abstract
Neurocognitive impairment (NCI) is one of the most relevant clinical manifestations of multiple sclerosis (MS). The profile of NCI and the structural and functional changes in the brain structures relevant for cognition in MS share some similarities to those in Alzheimer's disease (AD), the most common cause of neurocognitive disorders. Additionally, despite clear etiopathological differences between MS and AD, an accumulation of effector/memory CD8+ T cells and CD8+ tissue-resident memory T (Trm) cells in cognitively relevant brain structures of MS/AD patients, and higher frequency of effector/memory CD8+ T cells re-expressing CD45RA (TEMRA) with high capacity to secrete cytotoxic molecules and proinflammatory cytokines in their blood, were found. Thus, an active pathogenetic role of CD8+ T cells in the progression of MS and AD may be assumed. In this mini-review, findings supporting the putative role of CD8+ T cells in the pathogenesis of MS and AD are displayed, and putative mechanisms underlying their pathogenetic action are discussed. A special effort was made to identify the gaps in the current knowledge about the role of CD8+ T cells in the development of NCI to "catalyze" translational research leading to new feasible therapeutic interventions.
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Affiliation(s)
- Zorica Stojić-Vukanić
- Department of Microbiology and Immunology, University of Belgrade-Faculty of Pharmacy, Belgrade, Serbia
| | - Senka Hadžibegović
- Institut des Maladies Neurodégénératives, CNRS, UMR5293, Bordeaux, France.,Institut des Maladies Neurodégénératives, Université de Bordeaux, UMR5293, Bordeaux, France
| | - Olivier Nicole
- Institut des Maladies Neurodégénératives, CNRS, UMR5293, Bordeaux, France.,Institut des Maladies Neurodégénératives, Université de Bordeaux, UMR5293, Bordeaux, France
| | - Mirjana Nacka-Aleksić
- Department of Pathobiology, University of Belgrade-Faculty of Pharmacy, Belgrade, Serbia
| | - Sanja Leštarević
- Department of Pathobiology, University of Belgrade-Faculty of Pharmacy, Belgrade, Serbia
| | - Gordana Leposavić
- Department of Pathobiology, University of Belgrade-Faculty of Pharmacy, Belgrade, Serbia
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38
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Moyse E, Haddad M, Benlabiod C, Ramassamy C, Krantic S. Common Pathological Mechanisms and Risk Factors for Alzheimer's Disease and Type-2 Diabetes: Focus on Inflammation. Curr Alzheimer Res 2020; 16:986-1006. [PMID: 31692443 DOI: 10.2174/1567205016666191106094356] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 09/10/2019] [Accepted: 10/11/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Diabetes is considered as a risk factor for Alzheimer's Disease, but it is yet unclear whether this pathological link is reciprocal. Although Alzheimer's disease and diabetes appear as entirely different pathological entities affecting the Central Nervous System and a peripheral organ (pancreas), respectively, they share a common pathological core. Recent evidence suggests that in the pancreas in the case of diabetes, as in the brain for Alzheimer's Disease, the initial pathological event may be the accumulation of toxic proteins yielding amyloidosis. Moreover, in both pathologies, amyloidosis is likely responsible for local inflammation, which acts as a driving force for cell death and tissue degeneration. These pathological events are all inter-connected and establish a vicious cycle resulting in the progressive character of both pathologies. OBJECTIVE To address the literature supporting the hypothesis of a common pathological core for both diseases. DISCUSSION We will focus on the analogies and differences between the disease-related inflammatory changes in a peripheral organ, such as the pancreas, versus those observed in the brain. Recent evidence suggesting an impact of peripheral inflammation on neuroinflammation in Alzheimer's disease will be presented. CONCLUSION We propose that it is now necessary to consider whether neuroinflammation in Alzheimer's disease affects inflammation in the pancreas related to diabetes.
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Affiliation(s)
| | - Mohamed Haddad
- INRS-Centre Armand-Frappier Sante Biotechnologie, Laval, QC, Canada
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39
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CD8 + T cells are present at low levels in the white matter with physiological and pathological aging. Aging (Albany NY) 2020; 12:18928-18941. [PMID: 33049712 PMCID: PMC7732290 DOI: 10.18632/aging.104043] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 07/25/2020] [Indexed: 01/24/2023]
Abstract
The presence and functional role of T cell infiltration in human brain parenchyma with normal aging and neurodegeneration is still under intense debate. Recently, CD8+ cells have been shown to infiltrate the subventricular zone in humans and mice with a deleterious effect on neural stem cells. However, to which extent T cell infiltration in humans also occurs in other regions such as cortical areas and, especially, white matter (WM) has not yet been addressed. In this work, we report a low-grade infiltration of T cells (CD3+, CD4+ and CD8+) in the WM of aged individuals that is also observed at similar levels in patients with neurodegenerative disorders (Alzheimer´s disease). In particular, CD3+ and CD8+ cells were increased in perivascular and parenchymal WM and cortical regions (enthorinal cortex). These results reveal that T cell infiltration in brain parenchyma occurs with physiological and pathological aging in several regions, but it seems to be lower than in the subventricular zone neurogenic niche.
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40
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Moreno‐Valladares M, Moreno‐Cugnon L, Silva TM, Garcés JP, Saenz‐Antoñanzas A, Álvarez‐Satta M, Matheu A. CD8 + T cells are increased in the subventricular zone with physiological and pathological aging. Aging Cell 2020; 19:e13198. [PMID: 32741087 PMCID: PMC7511866 DOI: 10.1111/acel.13198] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 06/25/2020] [Accepted: 07/01/2020] [Indexed: 02/02/2023] Open
Abstract
Age-related cognitive decline and neurodegenerative diseases are associated with less functional neurogenic niches. It has been recently shown that aged subventricular zone (SVZ) suffers an infiltration of T cells, which affects neural stem cell activity in mice. Whether this occurs in human neurogenic niches or to which extent T-cell infiltration is also taking place in neurodegenerative diseases remains unknown. In this work, we studied the presence of T cells in both human neurogenic niches in young and old individuals. There was a significant increase in the number of CD3+ and CD8+ T cells in the SVZ of elderly individuals, which was not detected in the dentate gyrus. Moreover, we also found CD3+ and CD8+ T cells in the SVZ of individuals with neurodegenerative diseases. However, T-cell count was similar when compared non-neuropathological elderly with disease diagnosed patients. Our study reveals the infiltration of T cells in old human brains, particularly in the SVZ under non-pathological conditions and also in neurodegenerative contexts.
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Affiliation(s)
- Manuel Moreno‐Valladares
- Biodonostia Health Research Institute Group of Cellular Oncology San Sebastian Spain
- Pathology Department Donostia University Hospital San Sebastian Spain
| | - Leire Moreno‐Cugnon
- Biodonostia Health Research Institute Group of Cellular Oncology San Sebastian Spain
| | - Tulio Mateo Silva
- Pathology Department Donostia University Hospital San Sebastian Spain
| | - Juan Pablo Garcés
- Pathology Department Donostia University Hospital San Sebastian Spain
| | | | - María Álvarez‐Satta
- Biodonostia Health Research Institute Group of Cellular Oncology San Sebastian Spain
| | - Ander Matheu
- Biodonostia Health Research Institute Group of Cellular Oncology San Sebastian Spain
- CIBER of Frailty and Healthy Aging (CIBERfes) Carlos III Institute Madrid Spain
- IKERBASQUE Basque Foundation for Science Bilbao Spain
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41
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Dhanwani R, Pham J, Premlal ALR, Frazier A, Kumar A, Pero ME, Bartolini F, Dutra JR, Marder KS, Peters B, Sulzer D, Sette A, Lindestam Arlehamn CS. T Cell Responses to Neural Autoantigens Are Similar in Alzheimer's Disease Patients and Age-Matched Healthy Controls. Front Neurosci 2020; 14:874. [PMID: 32982670 PMCID: PMC7481378 DOI: 10.3389/fnins.2020.00874] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 07/27/2020] [Indexed: 01/03/2023] Open
Abstract
Alzheimer's disease (AD), a chronic multifactorial and complex neurodegenerative disorder is a leading cause of dementia. Recently, neuroinflammation has been hypothesized as a contributing factor to AD pathogenesis. The role of adaptive immune responses against neuronal antigens, which can either confer protection or induce damage in AD, has not been fully characterized. Here, we measured T cell responses to several potential antigens of neural origin including amyloid precursor protein (APP), amyloid beta (Aβ), tau, α-synuclein, and transactive response DNA binding protein (TDP-43) in patients with AD and age-matched healthy controls (HC). Antigen-specific T cell reactivity was detected for all tested antigens, and response to tau-derived epitopes was particularly strong, but no significant differences between individuals with AD and age-matched HC were identified. We also did not observe any correlation between the antigen-specific T cell responses and clinical variables including age, gender, years since diagnosis and cognitive score. Additionally, further characterization did not reveal any differences in the relative frequency of major Peripheral Blood Mononuclear Cells (PBMC) subsets, or in the expression of genes between AD patients and HC. These observations have not identified a key role of neuronal antigen-specific T cell responses in AD.
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Affiliation(s)
- Rekha Dhanwani
- Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, United States
| | - John Pham
- Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, United States
| | | | - April Frazier
- Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, United States
| | - Atul Kumar
- Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
| | - Maria Elena Pero
- Department of Pathology and Cell Biology, Columbia University, New York, NY, United States.,Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy
| | - Francesca Bartolini
- Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
| | - Juliana Rezende Dutra
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
| | - Karen S Marder
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
| | - Bjoern Peters
- Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, United States.,Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - David Sulzer
- Department of Neurology, New York State Psychiatric Institute, Columbia University, New York, NY, United States.,Department of Psychiatry and Pharmacology, New York State Psychiatric Institute, Columbia University, New York, NY, United States
| | - Alessandro Sette
- Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, United States.,Department of Medicine, University of California, San Diego, La Jolla, CA, United States
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42
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Liddelow SA, Marsh SE, Stevens B. Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime? Trends Immunol 2020; 41:820-835. [PMID: 32819809 DOI: 10.1016/j.it.2020.07.006] [Citation(s) in RCA: 165] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/10/2020] [Accepted: 07/11/2020] [Indexed: 02/08/2023]
Abstract
Microglia-astrocyte interactions represent a delicate balance affecting neural cell functions in health and disease. Tightly controlled to maintain homeostasis during physiological conditions, rapid and prolonged departures during disease, infection, and following trauma drive multiple outcomes: both beneficial and detrimental. Recent sequencing studies at the bulk and single-cell level in humans and rodents provide new insight into microglia-astrocyte communication in homeostasis and disease. However, the complex changing ways these two cell types functionally interact has been a barrier to understanding disease initiation, progression, and disease mechanisms. Single cell sequencing is providing new insights; however, many questions remain. Here, we discuss how to bridge transcriptional states to specific functions so we can develop therapies to mediate negative effects of altered microglia-astrocyte interactions.
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Affiliation(s)
- Shane A Liddelow
- Neuroscience Institute, NYU School of Medicine, New York, NY, USA; Department of Neuroscience and Physiology, NYU School of Medicine, New York, NY, USA; Department of Ophthalmology, NYU School of Medicine, New York, NY, USA.
| | - Samuel E Marsh
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Beth Stevens
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA., USA.
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43
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Rodríguez-Gómez JA, Kavanagh E, Engskog-Vlachos P, Engskog MK, Herrera AJ, Espinosa-Oliva AM, Joseph B, Hajji N, Venero JL, Burguillos MA. Microglia: Agents of the CNS Pro-Inflammatory Response. Cells 2020; 9:E1717. [PMID: 32709045 PMCID: PMC7407646 DOI: 10.3390/cells9071717] [Citation(s) in RCA: 222] [Impact Index Per Article: 44.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 07/14/2020] [Accepted: 07/15/2020] [Indexed: 12/21/2022] Open
Abstract
The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.
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Affiliation(s)
- José A. Rodríguez-Gómez
- Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; (J.A.R.-G.); (A.J.H.); (A.M.E.-O.); (J.L.V.)
- Department of Medical Physiology and Biophysics, Faculty of Medicine, University of Seville, 41009 Sevilla, Spain
| | - Edel Kavanagh
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain;
| | - Pinelopi Engskog-Vlachos
- Institute of Environmental Medicine, Toxicology Unit, Karolinska Institute, 17177 Stockholm, Sweden; (P.E.-V.); (B.J.)
| | - Mikael K.R. Engskog
- Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, 751 23 Uppsala, Sweden;
| | - Antonio J. Herrera
- Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; (J.A.R.-G.); (A.J.H.); (A.M.E.-O.); (J.L.V.)
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain;
| | - Ana M. Espinosa-Oliva
- Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; (J.A.R.-G.); (A.J.H.); (A.M.E.-O.); (J.L.V.)
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain;
| | - Bertrand Joseph
- Institute of Environmental Medicine, Toxicology Unit, Karolinska Institute, 17177 Stockholm, Sweden; (P.E.-V.); (B.J.)
| | - Nabil Hajji
- Division of Brain Sciences, The John Fulcher Molecular Neuro-Oncology Laboratory, Imperial College London, London W12 ONN, UK;
| | - José L. Venero
- Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; (J.A.R.-G.); (A.J.H.); (A.M.E.-O.); (J.L.V.)
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain;
| | - Miguel A. Burguillos
- Institute of Biomedicine of Seville (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/University of Seville, 41012 Seville, Spain; (J.A.R.-G.); (A.J.H.); (A.M.E.-O.); (J.L.V.)
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain;
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44
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Evans FL, Dittmer M, de la Fuente AG, Fitzgerald DC. Protective and Regenerative Roles of T Cells in Central Nervous System Disorders. Front Immunol 2019; 10:2171. [PMID: 31572381 PMCID: PMC6751344 DOI: 10.3389/fimmu.2019.02171] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 08/28/2019] [Indexed: 12/17/2022] Open
Abstract
Pathogenic mechanisms of T cells in several central nervous system (CNS) disorders are well-established. However, more recent studies have uncovered compelling beneficial roles of T cells in neurological diseases, ranging from tissue protection to regeneration. These divergent functions arise due to the diversity of T cell subsets, particularly CD4+ T cells. Here, we review the beneficial impact of T cell subsets in a range of neuroinflammatory and neurodegenerative diseases including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and CNS trauma. Both T cell-secreted mediators and direct cell contact-dependent mechanisms deliver neuroprotective, neuroregenerative and immunomodulatory signals in these settings. Understanding the molecular details of these beneficial T cell mechanisms will provide novel targets for therapeutic exploitation that can be applied to a range of neurological disorders.
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Affiliation(s)
- Frances L Evans
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Marie Dittmer
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Alerie G de la Fuente
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Denise C Fitzgerald
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
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45
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Pietronigro E, Zenaro E, Bianca VD, Dusi S, Terrabuio E, Iannoto G, Slanzi A, Ghasemi S, Nagarajan R, Piacentino G, Tosadori G, Rossi B, Constantin G. Blockade of α4 integrins reduces leukocyte-endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer's disease. Sci Rep 2019; 9:12055. [PMID: 31427644 PMCID: PMC6700124 DOI: 10.1038/s41598-019-48538-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 08/02/2019] [Indexed: 01/19/2023] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-β (Aβ) plaques, hyperphosphorylation of tau protein, and neuronal loss. Vascular inflammation and leukocyte trafficking may contribute to AD pathogenesis, and a better understanding of these inflammation mechanisms could therefore facilitate the development of new AD therapies. Here we show that T cells extravasate in the proximity of cerebral VCAM-1+ vessels in 3xTg-AD transgenic mice, which develop both Aβ and tau pathologies. The counter-ligand of VCAM-1 - α4β1 integrin, also known as very late antigen-4 (VLA-4) - was more abundant on circulating CD4+ T cells and was also expressed by a significant proportion of blood CD8+ T cells and neutrophils in AD mice. Intravital microscopy of the brain microcirculation revealed that α4 integrins control leukocyte-endothelial interactions in AD mice. Therapeutic targeting of VLA-4 using antibodies that specifically block α4 integrins improved the memory of 3xTg-AD mice compared to an isotype control. These antibodies also reduced neuropathological hallmarks of AD, including microgliosis, Aβ load and tau hyperphosphorylation. Our results demonstrate that α4 integrin-dependent leukocyte trafficking promotes cognitive impairment and AD neuropathology, suggesting that the blockade of α4 integrins may offer a new therapeutic strategy in AD.
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Affiliation(s)
| | - Elena Zenaro
- Department of Medicine, University of Verona, 37134, Verona, Italy
| | | | - Silvia Dusi
- Department of Medicine, University of Verona, 37134, Verona, Italy
| | | | - Giulia Iannoto
- Department of Medicine, University of Verona, 37134, Verona, Italy
| | - Anna Slanzi
- Department of Medicine, University of Verona, 37134, Verona, Italy
| | | | | | - Gennj Piacentino
- Department of Medicine, University of Verona, 37134, Verona, Italy
| | - Gabriele Tosadori
- Department of Medicine, University of Verona, 37134, Verona, Italy
- The Center for Biomedical Computing (CBMC), University of Verona, 37134, Verona, Italy
| | - Barbara Rossi
- Department of Medicine, University of Verona, 37134, Verona, Italy
| | - Gabriela Constantin
- Department of Medicine, University of Verona, 37134, Verona, Italy.
- The Center for Biomedical Computing (CBMC), University of Verona, 37134, Verona, Italy.
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46
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Lindestam Arlehamn CS, Garretti F, Sulzer D, Sette A. Roles for the adaptive immune system in Parkinson's and Alzheimer's diseases. Curr Opin Immunol 2019; 59:115-120. [PMID: 31430650 DOI: 10.1016/j.coi.2019.07.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 04/05/2019] [Accepted: 07/18/2019] [Indexed: 01/14/2023]
Abstract
Neurodegenerative diseases, such as Parkinson's and Alzheimer's, affect millions of people and pose major personal and socioeconomic burdens. The causes of neurodegeneration are mostly unknown, although current efforts have described an autoimmune aspect to these diseases. Here we discuss recent findings that shed light on the involvement of the adaptive immune system in Parkinson's and Alzheimer's diseases, and provide a model and outlook for further investigation of T cell responses in neurodegenerative disease. We focus on the identification of T cell epitopes from proteins involved in disease pathogenesis and describe the identification of α-synuclein-specific epitopes in Parkinson's disease which provided a crucial link between disease susceptibility and T cell recognition.
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Affiliation(s)
| | - Francesca Garretti
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - David Sulzer
- Departments for Neurology, Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY 10032, USA
| | - Alessandro Sette
- Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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47
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Maezawa I, Nguyen HM, Di Lucente J, Jenkins DP, Singh V, Hilt S, Kim K, Rangaraju S, Levey AI, Wulff H, Jin LW. Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer's disease: preclinical proof of concept. Brain 2019; 141:596-612. [PMID: 29272333 DOI: 10.1093/brain/awx346] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 10/30/2017] [Indexed: 12/14/2022] Open
Abstract
Microglia significantly contribute to the pathophysiology of Alzheimer's disease but an effective microglia-targeted therapeutic approach is not yet available clinically. The potassium channels Kv1.3 and Kir2.1 play important roles in regulating immune cell functions and have been implicated by in vitro studies in the 'M1-like pro-inflammatory' or 'M2-like anti-inflammatory' state of microglia, respectively. We here found that amyloid-β oligomer-induced expression of Kv1.3 and Kir2.1 in cultured primary microglia. Likewise, ex vivo microglia acutely isolated from the Alzheimer's model 5xFAD mice co-expressed Kv1.3 and Kir2.1 as well as markers traditionally associated with M1 and M2 activation suggesting that amyloid-β oligomer induces a microglial activation state that is more complex than previously thought. Using the orally available, brain penetrant small molecule Kv1.3 blocker PAP-1 as a tool, we showed that pro-inflammatory and neurotoxic microglial responses induced by amyloid-β oligomer required Kv1.3 activity in vitro and in hippocampal slices. Since we further observed that Kv1.3 was highly expressed in microglia of transgenic Alzheimer's mouse models and human Alzheimer's disease brains, we hypothesized that pharmacological Kv1.3 inhibition could mitigate the pathology induced by amyloid-β aggregates. Indeed, treating APP/PS1 transgenic mice with a 5-month oral regimen of PAP-1, starting at 9 months of age, when the animals already manifest cognitive deficits and amyloid pathology, reduced neuroinflammation, decreased cerebral amyloid load, enhanced hippocampal neuronal plasticity, and improved behavioural deficits. The observed decrease in cerebral amyloid deposition was consistent with the in vitro finding that PAP-1 enhanced amyloid-β uptake by microglia. Collectively, these results provide proof-of-concept data to advance Kv1.3 blockers to Alzheimer's disease clinical trials.
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Affiliation(s)
- Izumi Maezawa
- Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, 2805 50th Street, Sacramento, CA 95817, USA
| | - Hai M Nguyen
- Department of Pharmacology, University of California Davis, 451 Health Sciences Drive, Davis, CA 95616, USA
| | - Jacopo Di Lucente
- Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, 2805 50th Street, Sacramento, CA 95817, USA
| | - David Paul Jenkins
- Department of Pharmacology, University of California Davis, 451 Health Sciences Drive, Davis, CA 95616, USA
| | - Vikrant Singh
- Department of Pharmacology, University of California Davis, 451 Health Sciences Drive, Davis, CA 95616, USA
| | - Silvia Hilt
- Department of Biochemistry and Molecular Medicine, University of California Davis, 2700 Stockton Blvd, Sacramento, CA 95817, USA
| | - Kyoungmi Kim
- Department of Public Health Sciences, University of California Davis, One Shields Avenue, Med Sci 1-C, Davis, CA 95616, USA
| | - Srikant Rangaraju
- Department of Neurology and Alzheimer's Disease Research Center, Emory University, 201 Dowman Drive, Atlanta, GA 30322, USA
| | - Allan I Levey
- Department of Neurology and Alzheimer's Disease Research Center, Emory University, 201 Dowman Drive, Atlanta, GA 30322, USA
| | - Heike Wulff
- Department of Pharmacology, University of California Davis, 451 Health Sciences Drive, Davis, CA 95616, USA
| | - Lee-Way Jin
- Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, 2805 50th Street, Sacramento, CA 95817, USA.,Alzheimer's Disease Center, University of California Davis Medical Center, 4860 Y Street, Suite 3900, Sacramento, CA 95817, USA
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48
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Dionisio-Santos DA, Olschowka JA, O'Banion MK. Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer's disease. J Neuroinflammation 2019; 16:74. [PMID: 30953557 PMCID: PMC6449993 DOI: 10.1186/s12974-019-1453-0] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 03/18/2019] [Indexed: 12/21/2022] Open
Abstract
Neuroinflammation is considered one of the cardinal features of Alzheimer’s disease (AD). Neuritic plaques composed of amyloid β and neurofibrillary tangle-laden neurons are surrounded by reactive astrocytes and microglia. Exposure of microglia, the resident myeloid cell of the CNS, to amyloid β causes these cells to acquire an inflammatory phenotype. While these reactive microglia are important to contain and phagocytose amyloid plaques, their activated phenotype impacts CNS homeostasis. In rodent models, increased neuroinflammation promoted by overexpression of proinflammatory cytokines can cause an increase in hyperphosphorylated tau and a decrease in hippocampal function. The peripheral immune system can also play a detrimental or beneficial role in CNS inflammation. Systemic inflammation can increase the risk of developing AD dementia, and chemokines released directly by microglia or indirectly by endothelial cells can attract monocytes and T lymphocytes to the CNS. These peripheral immune cells can aid in amyloid β clearance or modulate microglia responses, depending on the cell type. As such, several groups have targeted the peripheral immune system to modulate chronic neuroinflammation. In this review, we focus on the interplay of immunomodulating factors and cell types that are being investigated as possible therapeutic targets for the treatment or prevention of AD.
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Affiliation(s)
- Dawling A Dionisio-Santos
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 603, Rochester, NY, 14642, USA
| | - John A Olschowka
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 603, Rochester, NY, 14642, USA
| | - M Kerry O'Banion
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 603, Rochester, NY, 14642, USA.
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49
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Nichols MR, St-Pierre MK, Wendeln AC, Makoni NJ, Gouwens LK, Garrad EC, Sohrabi M, Neher JJ, Tremblay ME, Combs CK. Inflammatory mechanisms in neurodegeneration. J Neurochem 2019; 149:562-581. [PMID: 30702751 DOI: 10.1111/jnc.14674] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 12/21/2018] [Accepted: 01/28/2019] [Indexed: 12/28/2022]
Abstract
This review discusses the profound connection between microglia, neuroinflammation, and Alzheimer's disease (AD). Theories have been postulated, tested, and modified over several decades. The findings have further bolstered the belief that microglia-mediated inflammation is both a product and contributor to AD pathology and progression. Distinct microglia phenotypes and their function, microglial recognition and response to protein aggregates in AD, and the overall role of microglia in AD are areas that have received considerable research attention and yielded significant results. The following article provides a historical perspective of microglia, a detailed discussion of multiple microglia phenotypes including dark microglia, and a review of a number of areas where microglia intersect with AD and other pathological neurological processes. The overall breadth of important discoveries achieved in these areas significantly strengthens the hypothesis that neuroinflammation plays a key role in AD. Future determination of the exact mechanisms by which microglia respond to, and attempt to mitigate, protein aggregation in AD may lead to new therapeutic strategies.
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Affiliation(s)
- Michael R Nichols
- Department of Chemistry & Biochemistry, University of Missouri-St. Louis, St. Louis, Missouri, USA
| | - Marie-Kim St-Pierre
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, Quebec, Canada.,Département de médecine moléculaire, Université Laval, Québec, Quebec, Canada
| | - Ann-Christin Wendeln
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.,Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Nyasha J Makoni
- Department of Chemistry & Biochemistry, University of Missouri-St. Louis, St. Louis, Missouri, USA
| | - Lisa K Gouwens
- Department of Chemistry & Biochemistry, University of Missouri-St. Louis, St. Louis, Missouri, USA
| | - Evan C Garrad
- Department of Chemistry & Biochemistry, University of Missouri-St. Louis, St. Louis, Missouri, USA
| | - Mona Sohrabi
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, USA
| | - Jonas J Neher
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.,Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Marie-Eve Tremblay
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, Quebec, Canada.,Département de médecine moléculaire, Université Laval, Québec, Quebec, Canada
| | - Colin K Combs
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, USA
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50
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Herman FJ, Simkovic S, Pasinetti GM. Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets. Br J Pharmacol 2019; 176:3558-3584. [PMID: 30632147 DOI: 10.1111/bph.14569] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 11/26/2018] [Accepted: 12/04/2018] [Indexed: 12/12/2022] Open
Abstract
Dysfunctional immune activity is a physiological component of both Alzheimer's disease (AD) and major depressive disorder (MDD). The extent to which altered immune activity influences the development of their respective cognitive symptoms and neuropathologies remains under investigation. It is evident, however, that immune activity affects neuronal function and circuit integrity. In both disorders, alterations are present in similar immune networks and neuroendocrine signalling pathways, immune responses persist in overlapping neuroanatomical locations, and morphological and structural irregularities are noted in similar domains. Epidemiological studies have also linked the two disorders, and their genetic and environmental risk factors intersect along immune-activating pathways and can be synonymous with one another. While each of these disorders individually contains a large degree of heterogeneity, their shared immunological components may link distinct phenotypes within each disorder. This review will therefore highlight the shared immune pathways of AD and MDD, their overlapping neuroanatomical features, and previously applied, as well as novel, approaches to pharmacologically manipulate immune pathways, in each neurological condition. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.
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Affiliation(s)
- Francis J Herman
- Department of Neurology, Mount Sinai School of Medicine, New York City, New York, USA
| | - Sherry Simkovic
- Department of Neurology, Mount Sinai School of Medicine, New York City, New York, USA
| | - Giulio M Pasinetti
- Department of Neurology, Mount Sinai School of Medicine, New York City, New York, USA.,Geriatrics Research. Education, and Clinical Center, JJ Peters VA Medical Center, Bronx, New York, USA
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