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Saadh MJ, Ahmed HH, Kareem RA, Sanghvi G, Ganesan S, Agarwal M, Kaur P, Taher WM, Alwan M, Jawad MJ, Hamad AK. Short-chain fatty acids in Huntington's disease: Mechanisms of action and their therapeutic implications. Pharmacol Biochem Behav 2025; 249:173972. [PMID: 39983928 DOI: 10.1016/j.pbb.2025.173972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 02/10/2025] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and emotional instability, primarily resulting from the abnormal accumulation of mutant huntingtin protein. Growing research highlights the role of intestinal microbiota and their metabolites, particularly short-chain fatty acids (SCFAs), in modulating HD progression. SCFAs, including acetate, propionate, and butyrate, are produced by gut bacteria through dietary fiber fermentation and are recognized for their neuroprotective properties. Evidence suggests that SCFAs regulate neuroinflammation, neuronal communication, and metabolic functions within the central nervous system (CNS). In HD, these compounds may support neuronal health, reduce oxidative stress, and enhance blood-brain barrier (BBB) integrity. Their mechanisms of action involve binding to G-protein-coupled receptors (GPCRs) and modulating gene expression through epigenetic pathways, underscoring their therapeutic potential. This analysis examines the significance of SCFAs in HD, emphasizing the gut-brain axis and the benefits of dietary interventions aimed at modifying gut microbiota composition and promoting SCFA production. Further research into these pathways may pave the way for novel HD management strategies and improved therapeutic outcomes.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | | | | | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot 360003, Gujarat, India
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Mohit Agarwal
- Department of Pharmaceutical Chemistry, NIMS Institute of Pharmacy, NIMS University, Rajasthan, Jaipur,302131, India
| | - Parjinder Kaur
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali 140307, Punjab, India
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
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Fung JN, Lee JD, Adam R, O'Sullivan JD, Woodruff TM. Peripheral and central elevation of IL-8 in patients with Huntington's disease. Mol Immunol 2025; 179:84-93. [PMID: 39923663 DOI: 10.1016/j.molimm.2025.02.003] [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: 06/03/2024] [Revised: 01/20/2025] [Accepted: 02/02/2025] [Indexed: 02/11/2025]
Abstract
OBJECTIVES Huntington's Disease (HD) is a debilitating neurodegenerative condition characterized by motor, cognitive and psychiatric abnormalities. Immune hyperactivity and dysregulation are common in HD. In addition to the central nervous system, HD patients exhibit systemic innate immune activation and inflammation, which has been shown to contribute to the pathogenic effects of the Huntingtin gene mutation. Upregulation of inflammatory mediators including interferon gamma (IFN-γ) and interleukin (IL)-8 has been observed in animal Huntington's disease models. However, studies on HD patients remain limited. METHODS In this study, serum samples from 58 HD patients and 59 age- and gender-matched healthy control individuals were analysed using a bead-based assay, that enabled simultaneous measurement of 13 cytokines and chemokines. Additionally, publicly available transcriptomic data from brain tissues of HD patients and controls were examined. RESULTS Our results confirm that IL-8 protein levels are significantly higher in HD patients compared to non-HD controls, with the highest levels observed in the moderate HD group. In the control group, we found significant positive correlations between IL-8 levels and both IL-17A and IL-10. However, these correlations were not observed in HD patients, where IL-8 levels were notably positively correlated with pro-inflammatory markers including IFNγ and IL-23. Interestingly, IL-17A levels demonstrated a negative correlation with disease parameters, including CAG trinucleotide repeat expansion and disease burden score. Furthermore, cytokines and chemokines such as IFNγ and monocyte chemoattractant protein 1 (MCP-1; CCL2) demonstrated positive correlations with the same disease parameters. In-depth analysis of publicly available bulk RNAseq, and single-nucleus RNA-sequencing (snRNAseq) data from two key HD-affected brain regions- the prefrontal cortex and striatum revealed that IL-8 expression is significantly increased in cortex samples from individuals with HD compared to non-HD controls. Moreover, snRNAseq data in the striatum showed higher IL-8 expression in HD patients than in non-HD controls, with a predominant expression in microglia. CONCLUSION Overall, our findings support an upregulation of IL-8 in patients with HD, evident in both central degenerating brain regions, and peripheral blood samples. We identified unique immunological signatures associated with the severity of HD and provide potential biomarkers that may reflect immune-pathological mechanisms in HD patients.
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Affiliation(s)
- Jenny N Fung
- School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia
| | - John D Lee
- School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia
| | - Robert Adam
- Neurology Department, Royal Brisbane and Women's Hospital, Herston, Brisbane, QLD 4029, Australia; Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, Brisbane, QLD 4029, Australia
| | - John D O'Sullivan
- Neurology Department, Royal Brisbane and Women's Hospital, Herston, Brisbane, QLD 4029, Australia; Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, Brisbane, QLD 4029, Australia.
| | - Trent M Woodruff
- School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia; Queensland Brain Institute, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.
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Li X, Tong H, Xu S, Zhou G, Yang T, Yin S, Yang S, Li X, Li S. Neuroinflammatory Proteins in Huntington's Disease: Insights into Mechanisms, Diagnosis, and Therapeutic Implications. Int J Mol Sci 2024; 25:11787. [PMID: 39519337 PMCID: PMC11546928 DOI: 10.3390/ijms252111787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 10/30/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024] Open
Abstract
Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a CAG tract expansion in the huntingtin gene (HTT). HD is characterized by involuntary movements, cognitive decline, and behavioral changes. Pathologically, patients with HD show selective striatal neuronal vulnerability at the early disease stage, although the mutant protein is ubiquitously expressed. Activation of the immune system and glial cell-mediated neuroinflammatory responses are early pathological features and have been found in all neurodegenerative diseases (NDDs), including HD. However, the role of inflammation in HD, as well as its therapeutic significance, has been less extensively studied compared to other NDDs. This review highlights the significantly elevated levels of inflammatory proteins and cellular markers observed in various HD animal models and HD patient tissues, emphasizing the critical roles of microglia, astrocytes, and oligodendrocytes in mediating neuroinflammation in HD. Moreover, it expands on recent discoveries related to the peripheral immune system's involvement in HD. Although current immunomodulatory treatments and inflammatory biomarkers for adjunctive diagnosis in HD are limited, targeting inflammation in combination with other therapies, along with comprehensive personalized treatment approaches, shows promising therapeutic potential.
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Affiliation(s)
- Xinhui Li
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (X.L.); (H.T.); (S.X.); (G.Z.); (T.Y.); (S.Y.); (S.Y.); (X.L.)
| | - Huichun Tong
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (X.L.); (H.T.); (S.X.); (G.Z.); (T.Y.); (S.Y.); (S.Y.); (X.L.)
- Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Shuying Xu
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (X.L.); (H.T.); (S.X.); (G.Z.); (T.Y.); (S.Y.); (S.Y.); (X.L.)
| | - Gongke Zhou
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (X.L.); (H.T.); (S.X.); (G.Z.); (T.Y.); (S.Y.); (S.Y.); (X.L.)
| | - Tianqi Yang
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (X.L.); (H.T.); (S.X.); (G.Z.); (T.Y.); (S.Y.); (S.Y.); (X.L.)
| | - Shurui Yin
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (X.L.); (H.T.); (S.X.); (G.Z.); (T.Y.); (S.Y.); (S.Y.); (X.L.)
| | - Sitong Yang
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (X.L.); (H.T.); (S.X.); (G.Z.); (T.Y.); (S.Y.); (S.Y.); (X.L.)
| | - Xiaojiang Li
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (X.L.); (H.T.); (S.X.); (G.Z.); (T.Y.); (S.Y.); (S.Y.); (X.L.)
| | - Shihua Li
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; (X.L.); (H.T.); (S.X.); (G.Z.); (T.Y.); (S.Y.); (S.Y.); (X.L.)
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Young AP, Denovan-Wright EM. Microglia-mediated neuron death requires TNF and is exacerbated by mutant Huntingtin. Pharmacol Res 2024; 209:107443. [PMID: 39362509 DOI: 10.1016/j.phrs.2024.107443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 09/28/2024] [Accepted: 09/28/2024] [Indexed: 10/05/2024]
Abstract
Microglia, the resident immune cells of the brain, regulate the balance of inflammation in the central nervous system under healthy and pathogenic conditions. Huntington's disease (HD) is a chronic neurodegenerative disease characterized by activated microglia and elevated concentrations of pro-inflammatory cytokines within the brain. Chronic hyperactivation of microglia is associated with brain pathology and eventual neuron death. However, it is unclear which specific cytokines are required for neuron death and whether HD neurons may be hypersensitive to neuroinflammation. We assessed the profile of microglia-secreted proteins in response to LPS and IFNγ, and a conditioned media paradigm was used to examine the effects of these secreted proteins on cultured neuronal cells. STHdhQ7/Q7 and STHdhQ111/Q111 neuronal cells were used to model wild-type and HD neurons, respectively. We determined that STHdhQ111/Q111 cells were hypersensitive to pro-inflammatory factors secreted by microglia, and that TNF was required to induce neuronal death. Microglia-mediated neuronal death could be effectively halted through the use of JAK-STAT or TNF inhibitors which supported the requirement for TNF as well as IFNγ in the process of secondary neurotoxicity. Further data derived from human HD patients as well as HD mice were suggestive of enhanced receptor density for TNF (TNFR1) and IFNγ (IFNGR) which could sensitize the HD brain to these cytokines. This highlights several potential mechanisms by which microglia may induce neuronal death and suggests that these mechanisms may be upregulated in the brain of HD patients.
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Affiliation(s)
- Alexander P Young
- Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
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Bøstrand SMK, Seeker LA, Bestard-Cuche N, Kazakou NL, Jäkel S, Kenkhuis B, Henderson NC, de Bot ST, van Roon-Mom WMC, Priller J, Williams A. Mapping the glial transcriptome in Huntington's disease using snRNAseq: selective disruption of glial signatures across brain regions. Acta Neuropathol Commun 2024; 12:165. [PMID: 39428482 PMCID: PMC11492505 DOI: 10.1186/s40478-024-01871-3] [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: 09/26/2024] [Accepted: 09/29/2024] [Indexed: 10/22/2024] Open
Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from donors with HD and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight possible mechanisms that characterise the glial contribution to HD pathology including depletion of myelinating oligodendrocytes, an oligodendrocyte-specific upregulation of the calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 A (PDE1A) and an upregulation of molecular chaperones as a cross-glial signature and a potential adaptive response to the accumulation of mutant huntingtin (mHTT). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease.
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Affiliation(s)
- Sunniva M K Bøstrand
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Luise A Seeker
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Nadine Bestard-Cuche
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Nina-Lydia Kazakou
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Sarah Jäkel
- Institute for Stroke and Dementia Research, Ludwig-Maximilians-Universität, LMU Hospital, Munich, Germany
| | - Boyd Kenkhuis
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Neil C Henderson
- Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, UK
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Susanne T de Bot
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Josef Priller
- CCBS and UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
- Department of Psychiatry and Psychotherapy, School of Medicine and Health, TU Munich, Munich, Germany.
- Neuropsychiatry and DZNE, Charité Universitätsmedizin Berlin, Berlin, Germany.
| | - Anna Williams
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
- CCBS and UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
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D'Egidio F, Castelli V, d'Angelo M, Ammannito F, Quintiliani M, Cimini A. Brain incoming call from glia during neuroinflammation: Roles of extracellular vesicles. Neurobiol Dis 2024; 201:106663. [PMID: 39251030 DOI: 10.1016/j.nbd.2024.106663] [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: 06/03/2024] [Revised: 09/04/2024] [Accepted: 09/06/2024] [Indexed: 09/11/2024] Open
Abstract
The functionality of the central nervous system (CNS) relies on the connection, integration, and the exchange of information among neural cells. The crosstalk among glial cells and neurons is pivotal for a series of neural functions, such as development of the nervous system, electric conduction, synaptic transmission, neural circuit establishment, and brain homeostasis. Glial cells are crucial players in the maintenance of brain functionality in physiological and disease conditions. Neuroinflammation is a common pathological process in various brain disorders, such as neurodegenerative diseases, and infections. Glial cells, including astrocytes, microglia, and oligodendrocytes, are the main mediators of neuroinflammation, as they can sense and respond to brain insults by releasing pro-inflammatory or anti-inflammatory factors. Recent evidence indicates that extracellular vesicles (EVs) are pivotal players in the intercellular communication that underlies physiological and pathological processes. In particular, glia-derived EVs play relevant roles in modulating neuroinflammation, either by promoting or inhibiting the activation of glial cells and neurons, or by facilitating the clearance or propagation of pathogenic proteins. The involvement of EVs in neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Multiple Sclerosis (MS)- which share hallmarks such as neuroinflammation and oxidative stress to DNA damage, alterations in neurotrophin levels, mitochondrial impairment, and altered protein dynamics- will be dissected, showing how EVs act as pivotal cell-cell mediators of toxic stimuli, thereby propagating degeneration and cell death signaling. Thus, this review focuses on the EVs secreted by microglia, astrocytes, oligodendrocytes and in neuroinflammatory conditions, emphasizing on their effects on neurons and on central nervous system functions, considering both their beneficial and detrimental effects.
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Affiliation(s)
- Francesco D'Egidio
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo"
| | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo"
| | - Michele d'Angelo
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo".
| | - Fabrizio Ammannito
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo"
| | - Massimiliano Quintiliani
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo"
| | - Annamaria Cimini
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy 67100, Via Vetoio - Coppito1, Building "Renato Ricamo"
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Samuel Olajide T, Oyerinde TO, Omotosho OI, Okeowo OM, Olajide OJ, Ijomone OM. Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities. NEUROPROTECTION 2024; 2:182-195. [PMID: 39364217 PMCID: PMC11449118 DOI: 10.1002/nep3.56] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 06/03/2024] [Indexed: 10/05/2024]
Abstract
The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.
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Affiliation(s)
- Tobiloba Samuel Olajide
- Laboratory for Experimental and Translational Neurobiology, University of Medical Sciences, Ondo, Ondo, Nigeria
| | - Toheeb O. Oyerinde
- Laboratory for Experimental and Translational Neurobiology, University of Medical Sciences, Ondo, Ondo, Nigeria
| | - Omolabake I. Omotosho
- Laboratory for Experimental and Translational Neurobiology, University of Medical Sciences, Ondo, Ondo, Nigeria
| | - Oritoke M. Okeowo
- Laboratory for Experimental and Translational Neurobiology, University of Medical Sciences, Ondo, Ondo, Nigeria
- Department of Physiology, School of Basic Medical Science, Federal University of Technology, Akure, Ondo, Nigeria
| | - Olayemi J. Olajide
- Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Quebec, Canada
- Division of Neurobiology, Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Kwara, Nigeria
| | - Omamuyouwi M. Ijomone
- Laboratory for Experimental and Translational Neurobiology, University of Medical Sciences, Ondo, Ondo, Nigeria
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA
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Tan AYS, Tippett LJ, Turner CP, Swanson MEV, Park TIH, Curtis MA, Faull RLM, Dragunow M, Singh-Bains MK. Microglial proliferation and astrocytic protein alterations in the human Huntington's disease cortex. Neurobiol Dis 2024; 198:106554. [PMID: 38844243 DOI: 10.1016/j.nbd.2024.106554] [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: 03/20/2024] [Revised: 05/28/2024] [Accepted: 06/03/2024] [Indexed: 06/14/2024] Open
Abstract
Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis both contribute to basal ganglia pathology, the contribution of gliosis and potential factors driving glial activity in the human HD cerebral cortex is less understood. Our study aims to identify nuanced indicators of gliosis in HD which is challenging to identify in the severely degenerated basal ganglia, by investigating the middle temporal gyrus (MTG), a cortical region previously documented to demonstrate milder neuronal loss. Immunohistochemistry was conducted on MTG paraffin-embedded tissue microarrays (TMAs) comprising 29 HD and 35 neurologically normal cases to compare the immunoreactivity patterns of key astrocytic proteins (glial fibrillary acidic protein, GFAP; inwardly rectifying potassium channel 4.1, Kir4.1; glutamate transporter-1, GLT-1; aquaporin-4, AQP4), key microglial proteins (ionised calcium-binding adapter molecule-1, IBA-1; human leukocyte antigen (HLA)-DR; transmembrane protein 119, TMEM119; purinergic receptor P2RY12, P2RY12), and indicators of proliferation (Ki-67; proliferative cell nuclear antigen, PCNA). Our findings demonstrate an upregulation of GFAP+ protein expression attributed to the presence of more GFAP+ expressing cells in HD, which correlated with greater cortical mutant huntingtin (mHTT) deposition. In contrast, Kir4.1, GLT-1, and AQP4 immunoreactivity levels were unchanged in HD. We also demonstrate an increased number of IBA-1+ and TMEM119+ microglia with somal enlargement. IBA-1+, TMEM119+, and P2RY12+ reactive microglia immunophenotypes were also identified in HD, evidenced by the presence of rod-shaped, hypertrophic, and dystrophic microglia. In HD cases, IBA-1+ cells contained either Ki-67 or PCNA, whereas GFAP+ astrocytes were devoid of proliferative nuclei. These findings suggest cortical microgliosis may be driven by proliferation in HD, supporting the hypothesis of microglial proliferation as a feature of HD pathophysiology. In contrast, astrocytes in HD demonstrate an altered GFAP expression profile that is associated with the degree of mHTT deposition.
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Affiliation(s)
- Adelie Y S Tan
- Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Auckland 1023, New Zealand
| | - Lynette J Tippett
- Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; School of Psychology, University of Auckland, Auckland 1023, New Zealand
| | - Clinton P Turner
- Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Department of Anatomical Pathology, LabPlus, Auckland City Hospital, Auckland 1023, New Zealand
| | - Molly E V Swanson
- Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; School of Biological Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Thomas I H Park
- Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland 1023, New Zealand
| | - Maurice A Curtis
- Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Auckland 1023, New Zealand
| | - Richard L M Faull
- Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Auckland 1023, New Zealand
| | - Mike Dragunow
- Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland 1023, New Zealand.
| | - Malvindar K Singh-Bains
- Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Department of Anatomy and Medical Imaging, University of Auckland, Auckland 1023, New Zealand.
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Anwar MM, Pérez-Martínez L, Pedraza-Alva G. Exploring the Significance of Microglial Phenotypes and Morphological Diversity in Neuroinflammation and Neurodegenerative Diseases: From Mechanisms to Potential Therapeutic Targets. Immunol Invest 2024; 53:891-946. [PMID: 38836373 DOI: 10.1080/08820139.2024.2358446] [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] [Indexed: 06/06/2024]
Abstract
Studying various microglial phenotypes and their functions in neurodegenerative diseases is crucial due to the intricate nature of their phenomics and their vital immunological role. Microglia undergo substantial phenomic changes, encompassing morphological, transcriptional, and functional aspects, resulting in distinct cell types with diverse structures, functions, properties, and implications. The traditional classification of microglia as ramified, M1 (proinflammatory), or M2 (anti-inflammatory) phenotypes is overly simplistic, failing to capture the wide range of recently identified microglial phenotypes in various brain regions affected by neurodegenerative diseases. Altered and activated microglial phenotypes deviating from the typical ramified structure are significant features of many neurodegenerative conditions. Understanding the precise role of each microglial phenotype is intricate and sometimes contradictory. This review specifically focuses on elucidating recent modifications in microglial phenotypes within neurodegenerative diseases. Recognizing the heterogeneity of microglial phenotypes in diseased states can unveil novel therapeutic strategies for targeting microglia in neurodegenerative diseases. Moreover, the exploration of the use of healthy isolated microglia to mitigate disease progression has provided an innovative perspective. In conclusion, this review discusses the dynamic landscape of mysterious microglial phenotypes, emphasizing the need for a nuanced understanding to pave the way for innovative therapeutic strategies for neurodegenerative diseases.
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Affiliation(s)
- Mai M Anwar
- Department of Biochemistry, National Organization for Drug Control and Research (NODCAR)/Egyptian Drug Authority (EDA), Cairo, Egypt
| | - Leonor Pérez-Martínez
- Neuroimmunobiology Laboratory, Department of Molecular Medicine and Bioprocesses, Institute of Biotechnology, National Autonomous University of Mexico, Cuernavaca, Morelos, Mexico
| | - Gustavo Pedraza-Alva
- Neuroimmunobiology Laboratory, Department of Molecular Medicine and Bioprocesses, Institute of Biotechnology, National Autonomous University of Mexico, Cuernavaca, Morelos, Mexico
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Field SE, Curle AJ, Barker RA. Inflammation and Huntington's disease - a neglected therapeutic target? Expert Opin Investig Drugs 2024; 33:451-467. [PMID: 38758356 DOI: 10.1080/13543784.2024.2348738] [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: 12/19/2023] [Accepted: 04/24/2024] [Indexed: 05/18/2024]
Abstract
INTRODUCTION Huntington's Disease (HD) is a genetic neurodegenerative disease for which there is currently no disease-modifying treatment. One of several underlying mechanisms proposed to be involved in HD pathogenesis is inflammation; there is now accumulating evidence that the immune system may play an integral role in disease pathology and progression. As such, modulation of the immune system could be a potential therapeutic target for HD. AREAS COVERED To date, the number of trials targeting immune aspects of HD has been limited. However, targeting it, may have great advantages over other therapeutic areas, given that many drugs already exist that have actions in this system coupled to the fact that inflammation can be measured both peripherally and, to some extent, centrally using CSF and PET imaging. In this review, we look at evidence that the immune system and the newly emerging area of the microbiome are altered in HD patients, and then present and discuss clinical trials that have targeted different parts of the immune system. EXPERT OPINION We then conclude by discussing how this field might develop going forward, focusing on the role of imaging and other biomarkers to monitor central immune activation and response to novel treatments in HD.
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Affiliation(s)
- Sophie E Field
- Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, and MRC-WT Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Annabel J Curle
- Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, and MRC-WT Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Roger A Barker
- Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, and MRC-WT Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
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11
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Niso-Santano M, Fuentes JM, Galluzzi L. Immunological aspects of central neurodegeneration. Cell Discov 2024; 10:41. [PMID: 38594240 PMCID: PMC11004155 DOI: 10.1038/s41421-024-00666-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 03/02/2024] [Indexed: 04/11/2024] Open
Abstract
The etiology of various neurodegenerative disorders that mainly affect the central nervous system including (but not limited to) Alzheimer's disease, Parkinson's disease and Huntington's disease has classically been attributed to neuronal defects that culminate with the loss of specific neuronal populations. However, accumulating evidence suggests that numerous immune effector cells and the products thereof (including cytokines and other soluble mediators) have a major impact on the pathogenesis and/or severity of these and other neurodegenerative syndromes. These observations not only add to our understanding of neurodegenerative conditions but also imply that (at least in some cases) therapeutic strategies targeting immune cells or their products may mediate clinically relevant neuroprotective effects. Here, we critically discuss immunological mechanisms of central neurodegeneration and propose potential strategies to correct neurodegeneration-associated immunological dysfunction with therapeutic purposes.
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Affiliation(s)
- Mireia Niso-Santano
- Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Enfermería y Terapia Ocupacional, Universidad de Extremadura, Cáceres, Spain.
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas-Instituto de Salud Carlos III (CIBER-CIBERNED-ISCIII), Madrid, Spain.
- Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE), Cáceres, Spain.
| | - José M Fuentes
- Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Enfermería y Terapia Ocupacional, Universidad de Extremadura, Cáceres, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas-Instituto de Salud Carlos III (CIBER-CIBERNED-ISCIII), Madrid, Spain
- Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE), Cáceres, Spain
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
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12
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Li Q, Wu P, Du Q, Hanif U, Hu H, Li K. cGAS-STING, an important signaling pathway in diseases and their therapy. MedComm (Beijing) 2024; 5:e511. [PMID: 38525112 PMCID: PMC10960729 DOI: 10.1002/mco2.511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 02/15/2024] [Accepted: 02/21/2024] [Indexed: 03/26/2024] Open
Abstract
Since cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway was discovered in 2013, great progress has been made to elucidate the origin, function, and regulating mechanism of cGAS-STING signaling pathway in the past decade. Meanwhile, the triggering and transduction mechanisms have been continuously illuminated. cGAS-STING plays a key role in human diseases, particularly DNA-triggered inflammatory diseases, making it a potentially effective therapeutic target for inflammation-related diseases. Here, we aim to summarize the ancient origin of the cGAS-STING defense mechanism, as well as the triggers, transduction, and regulating mechanisms of the cGAS-STING. We will also focus on the important roles of cGAS-STING signal under pathological conditions, such as infections, cancers, autoimmune diseases, neurological diseases, and visceral inflammations, and review the progress in drug development targeting cGAS-STING signaling pathway. The main directions and potential obstacles in the regulating mechanism research and therapeutic drug development of the cGAS-STING signaling pathway for inflammatory diseases and cancers will be discussed. These research advancements expand our understanding of cGAS-STING, provide a theoretical basis for further exploration of the roles of cGAS-STING in diseases, and open up new strategies for targeting cGAS-STING as a promising therapeutic intervention in multiple diseases.
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Affiliation(s)
- Qijie Li
- Sichuan province Medical and Engineering Interdisciplinary Research Center of Nursing & Materials/Nursing Key Laboratory of Sichuan ProvinceWest China Hospital, Sichuan University/West China School of NursingSichuan UniversityChengduSichuanChina
| | - Ping Wu
- Department of Occupational DiseasesThe Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital)ChengduSichuanChina
| | - Qiujing Du
- Sichuan province Medical and Engineering Interdisciplinary Research Center of Nursing & Materials/Nursing Key Laboratory of Sichuan ProvinceWest China Hospital, Sichuan University/West China School of NursingSichuan UniversityChengduSichuanChina
| | - Ullah Hanif
- Sichuan province Medical and Engineering Interdisciplinary Research Center of Nursing & Materials/Nursing Key Laboratory of Sichuan ProvinceWest China Hospital, Sichuan University/West China School of NursingSichuan UniversityChengduSichuanChina
| | - Hongbo Hu
- Center for Immunology and HematologyState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Ka Li
- Sichuan province Medical and Engineering Interdisciplinary Research Center of Nursing & Materials/Nursing Key Laboratory of Sichuan ProvinceWest China Hospital, Sichuan University/West China School of NursingSichuan UniversityChengduSichuanChina
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13
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Bilal H, McDonald SJ, Stout JC, Harding IH. Associations of inflammatory cytokines and cortisol with nonmotor features of Huntington's disease. Ann Clin Transl Neurol 2024; 11:989-999. [PMID: 38356101 PMCID: PMC11021624 DOI: 10.1002/acn3.52016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/26/2023] [Accepted: 01/25/2024] [Indexed: 02/16/2024] Open
Abstract
OBJECTIVE Huntington's disease (HD) is an inherited neurodegenerative disease involving progressive motor abnormalities, cognitive decline, and psychiatric disturbances. Depression and cognitive difficulties are among the most impactful symptoms of HD, yet the pathogenesis of these symptoms is not fully understood. HD involves low-level chronic inflammation and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which are linked to depression and cognitive impairment in non-HD populations. However, previous research on the relationships of these pathologies with depression and cognition in HD is limited and inconsistent. METHODS Fifty-three adults with the HD gene expansion (30 premanifest and 23 manifest) completed measures of depression and cognitive functioning. Forty-eight out of 53 participants provided hair samples for quantification of cortisol, and 34 participants provided blood samples for quantification of peripheral inflammatory cytokines. We examined the associations of four cytokines (interleukin [IL]-6, IL-10, IL-1β, and tumor necrosis factor [TNF]-α) and cortisol levels with depression and cognitive scores. RESULTS In unadjusted models, higher levels of plasma IL-6, IL-10, and TNF-α correlated with higher depression scores, and higher levels of IL-10 and TNF-α correlated with poorer cognitive performance. After controlling for age, sex, and body mass index, only the correlations of IL-10 with depression and cognitive performance remained significant. No correlations were evident with hair cortisol. INTERPRETATIONS Peripheral inflammation is associated with depression symptoms and cognitive impairment in HD. Our findings suggest that interactions between the immune and nervous systems are important in HD, and highlight the potential of chronic inflammation as a therapeutic target in early stages of HD.
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Affiliation(s)
- Hiba Bilal
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, Victoria, Australia
| | - Stuart J McDonald
- Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria, Australia
| | - Julie C Stout
- School of Psychological Sciences, and Turner Institute for Brain and Mental Health, Monash University, Clayton, Victoria, Australia
| | - Ian H Harding
- Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria, Australia
- Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia
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14
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Singla M, Verma S, Thakur K, Goyal A, Sharma V, Sharma D, Porwal O, Subramaniyan V, Behl T, Singh SK, Dua K, Gupta G, Gupta S. From Plants to Therapies: Exploring the Pharmacology of Coumestrol for Neurological Conditions. Curr Med Chem 2024; 31:6855-6870. [PMID: 37921179 DOI: 10.2174/0109298673250784231011094322] [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: 03/22/2023] [Revised: 06/30/2023] [Accepted: 09/11/2023] [Indexed: 11/04/2023]
Abstract
Neurological disorders are possibly the most prevalent and have been identified to occur among individuals with autism beyond chance. These disorders encompass a diverse range of consequences with neurological causes and have been regarded as a major threat to public mental health. There is no tried-and-true approach for completely protecting the nervous system. Therefore, plant-derived compounds have developed significantly nowadays. Coumestrol (CML) is a potent isoflavone phytoestrogen with a protective effect against neurological dysfunction and has been discovered to be structurally and functionally similar to estrogen. In recent years, more research has been undertaken on phytoestrogens. This research demonstrates the biological complexity of phytoestrogens, which consist of multiple chemical families and function in various ways. This review aimed to explore recent findings on the most significant pharmacological advantages of CML by emphasising neurological benefits. Numerous CML extraction strategies and their pharmacological effects on various neurological disorders, including PD, AD, HD, anxiety, and cognitive impairments, were also documented.
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Affiliation(s)
- Madhav Singla
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Smriti Verma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Kiran Thakur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Ahsas Goyal
- Department of Pharmacy, Institute of Pharmaceutical Research, GLA University, U.P., India
| | - Vishal Sharma
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, 133207, India
| | - Diksha Sharma
- Department of Pharmacy, Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, 136119, India
| | - Omji Porwal
- Department of Pharmacognosy, Faculty of Pharmacy, Ishik University, Erbil, Kurdistan, Iraq
| | - Vetriselvan Subramaniyan
- Pharmacology Unit, Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Jalan Lagoon Selatan, Bandar Sunway, 47500 Selangor Darul Ehsan, Malaysia
| | - Tapan Behl
- Department of Pharmacy, School of Health Science and Technology, University of Petroleum Science and Energy Studies, Dehradun, Uttarakhand, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, Punjab, India
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, Australia
- Discipline of Pharmacy, Graduate School of Health, the University of Technology Sydney, Ultimo, NSW2007, Australia
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura 302017, Mahal Road, Jaipur, India
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Saurabh Gupta
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
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15
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Binda CS, Lelos MJ, Rosser AE, Massey TH. Using gene or cell therapies to treat Huntington's disease. HANDBOOK OF CLINICAL NEUROLOGY 2024; 205:193-215. [PMID: 39341655 DOI: 10.1016/b978-0-323-90120-8.00014-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Huntington's disease is caused by a CAG repeat expansion in the first exon of the HTT gene, leading to the production of gain-of-toxic-function mutant huntingtin protein species and consequent transcriptional dysregulation and disrupted cell metabolism. The brunt of the disease process is borne by the striatum from the earliest disease stages, with striatal atrophy beginning approximately a decade prior to the onset of neurologic signs. Although the expanded CAG repeat in the HTT gene is necessary and sufficient to cause HD, other genes can influence the age at onset of symptoms and how they progress. Many of these modifier genes have roles in DNA repair and are likely to modulate the stability of the CAG repeat in somatic cells. Currently, there are no disease-modifying treatments for HD that can be prescribed to patients and few symptomatic treatments, but there is a lot of interest in therapeutics that can target the pathogenic pathways at the DNA and RNA levels, some of which have reached the stage of human studies. In contrast, cell therapies aim to replace key neural cells lost to the disease process and/or to support the host vulnerable striatum by direct delivery of cells to the brain. Ultimately it may be possible to combine gene and cell therapies to both slow disease processes and provide some level of neural repair. In this chapter we consider the current status of these therapeutic strategies along with their prospects and challenges.
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Affiliation(s)
- Caroline S Binda
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom; UK Dementia Research Institute at Cardiff, Cardiff University, Cardiff, United Kingdom
| | - Mariah J Lelos
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Anne E Rosser
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom; BRAIN Unit, Neuroscience and Mental Health Research Institute, Cardiff, United Kingdom.
| | - Thomas H Massey
- Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom; UK Dementia Research Institute at Cardiff, Cardiff University, Cardiff, United Kingdom
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16
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Hobbs NZ, Papoutsi M, Delva A, Kinnunen KM, Nakajima M, Van Laere K, Vandenberghe W, Herath P, Scahill RI. Neuroimaging to Facilitate Clinical Trials in Huntington's Disease: Current Opinion from the EHDN Imaging Working Group. J Huntingtons Dis 2024; 13:163-199. [PMID: 38788082 PMCID: PMC11307036 DOI: 10.3233/jhd-240016] [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] [Accepted: 04/22/2024] [Indexed: 05/26/2024]
Abstract
Neuroimaging is increasingly being included in clinical trials of Huntington's disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials. Covering the key imaging modalities of structural-, functional- and diffusion- MRI, perfusion imaging, positron emission tomography, magnetic resonance spectroscopy, and magnetoencephalography, we address how neuroimaging can be used in HD trials to: 1) Aid patient selection, enrichment, stratification, and safety monitoring; 2) Demonstrate biodistribution, target engagement, and pharmacodynamics; 3) Provide evidence for disease modification; and 4) Understand brain re-organization following therapy. We also present the challenges of translating research methodology into clinical trial settings, including equipment requirements and cost, standardization of acquisition and analysis, patient burden and invasiveness, and interpretation of results. We conclude, that with appropriate consideration of modality, study design and analysis, imaging has huge potential to facilitate effective clinical trials in HD.
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Affiliation(s)
- Nicola Z. Hobbs
- HD Research Centre, UCL Institute of Neurology, UCL, London, UK
| | - Marina Papoutsi
- HD Research Centre, UCL Institute of Neurology, UCL, London, UK
- IXICO plc, London, UK
| | - Aline Delva
- Department of Neurosciences, KU Leuven, Belgium
- Department of Neurology, University Hospitals Leuven, Belgium
| | | | | | - Koen Van Laere
- Department of Imaging and Pathology, Nuclear Medicine and Molecular Imaging, KU Leuven, Belgium
- Division of Nuclear Medicine, University Hospitals Leuven, Belgium
| | - Wim Vandenberghe
- Department of Neurosciences, KU Leuven, Belgium
- Department of Neurology, University Hospitals Leuven, Belgium
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17
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Khoshnan A. Gut Microbiota as a Modifier of Huntington's Disease Pathogenesis. J Huntingtons Dis 2024; 13:133-147. [PMID: 38728199 PMCID: PMC11307070 DOI: 10.3233/jhd-240012] [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] [Accepted: 04/07/2024] [Indexed: 05/12/2024]
Abstract
Huntingtin (HTT) protein is expressed in most cell lineages, and the toxicity of mutant HTT in multiple organs may contribute to the neurological and psychiatric symptoms observed in Huntington's disease (HD). The proteostasis and neurotoxicity of mutant HTT are influenced by the intracellular milieu and responses to environmental signals. Recent research has highlighted a prominent role of gut microbiota in brain and immune system development, aging, and the progression of neurological disorders. Several studies suggest that mutant HTT might disrupt the homeostasis of gut microbiota (known as dysbiosis) and impact the pathogenesis of HD. Dysbiosis has been observed in HD patients, and in animal models of the disease it coincides with mutant HTT aggregation, abnormal behaviors, and reduced lifespan. This review article aims to highlight the potential toxicity of mutant HTT in organs and pathways within the microbiota-gut-immune-central nervous system (CNS) axis. Understanding the functions of Wild-Type (WT) HTT and the toxicity of mutant HTT in these organs and the associated networks may elucidate novel pathogenic pathways, identify biomarkers and peripheral therapeutic targets for HD.
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Affiliation(s)
- Ali Khoshnan
- Keck School of Medicine, Physiology and Neuroscience, University of Southern California, Los Angeles, CA, USA
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18
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Schoenberg PLA, Song AK, Mohr EM, Rogers BP, Peterson TE, Murphy BA. Increased microglia activation in late non-central nervous system cancer survivors links to chronic systemic symptomatology. Hum Brain Mapp 2023; 44:6001-6019. [PMID: 37751068 PMCID: PMC10619383 DOI: 10.1002/hbm.26491] [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: 02/03/2023] [Revised: 08/21/2023] [Accepted: 09/06/2023] [Indexed: 09/27/2023] Open
Abstract
Prolonged inflammatory expression within the central nervous system (CNS) is recognized by the brain as a molecular signal of "sickness", that has knock-on effects to the blood-brain barrier, brain-spinal barrier, blood-cerebrospinal fluid barrier, neuro-axonal structures, neurotransmitter activity, synaptic plasticity, neuroendocrine function, and resultant systemic symptomatology. It is concurred that the inflammatory process associated with cancer and cancer treatments underline systemic symptoms present in a large portion of survivors, although this concept is largely theoretical from disparate and indirect evidence and/or clinical anecdotal reports. We conducted a proof-of-concept study to link for the first time late non-CNS cancer survivors presenting chronic systemic symptoms and the presence of centralized inflammation, or neuroinflammation, using TSPO-binding PET tracer [11 C]-PBR28 to visualize microglial activation. We compared PBR28 SUVR in 10 non-CNS cancer survivors and 10 matched healthy controls. Our data revealed (1) microglial activation was significantly higher in caudate, temporal, and occipital regions in late non-central nervous system/CNS cancer survivors compared to healthy controls; (2) increased neuroinflammation in cancer survivors was not accompanied by significant differences in plasma cytokine markers of peripheral inflammation; (3) increased neuroinflammation was not accompanied by reduced fractional anisotropy, suggesting intact white matter microstructural integrity, a marker of neurovascular fiber tract organization; and (4) the presentation of chronic systemic symptoms in cancer survivors was significantly connected with microglial activation. We present the first data empirically supporting the concept of a peripheral-to-centralized inflammatory response in non-CNS cancer survivors, specifically those previously afflicted with head and neck cancer. Following resolution of the initial peripheral inflammation from the cancer/its treatments, in some cases damage/toxification to the central nervous system occurs, ensuing chronic systemic symptoms.
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Affiliation(s)
- Poppy L. A. Schoenberg
- Department of Physical Medicine and RehabilitationVanderbilt University Medical CenterNashvilleTennesseeUSA
- Osher Center for Integrative HealthVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Alexander K. Song
- Department of NeurologyVanderbilt University Medical CenterNashvilleTennesseeUSA
- Vanderbilt Brain InstituteVanderbilt UniversityNashvilleTennesseeUSA
| | - Emily M. Mohr
- Osher Center for Integrative HealthVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Baxter P. Rogers
- Vanderbilt Brain InstituteVanderbilt UniversityNashvilleTennesseeUSA
- Department of Radiology and Radiological SciencesVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Todd E. Peterson
- Vanderbilt Brain InstituteVanderbilt UniversityNashvilleTennesseeUSA
- Department of Radiology and Radiological SciencesVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Barbara A. Murphy
- Division of Hematology and OncologyVanderbilt‐Ingram Cancer CenterNashvilleTennesseeUSA
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19
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Stöberl N, Donaldson J, Binda CS, McAllister B, Hall-Roberts H, Jones L, Massey TH, Allen ND. Mutant huntingtin confers cell-autonomous phenotypes on Huntington's disease iPSC-derived microglia. Sci Rep 2023; 13:20477. [PMID: 37993517 PMCID: PMC10665390 DOI: 10.1038/s41598-023-46852-z] [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: 08/28/2023] [Accepted: 11/06/2023] [Indexed: 11/24/2023] Open
Abstract
Huntington's disease (HD) is a neurodegenerative disorder caused by a dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). Neuroinflammation and microglia have been implicated in HD pathology, however it has been unclear if mutant HTT (mHTT) expression has an adverse cell-autonomous effect on microglial function, or if they are only activated in response to the neurodegenerative brain environment in HD. To establish a human cell model of HD microglia function, we generated isogenic controls for HD patient-derived induced pluripotent stem cells (iPSC) with 109 CAG repeats (Q109). Q109 and isogenic Q22 iPSC, as well as non-isogenic Q60 and Q33 iPSC lines, were differentiated to iPSC-microglia. Our study supports a model of basal microglia dysfunction in HD leading to elevated pro-inflammatory cytokine production together with impaired phagocytosis and endocytosis capacity, in the absence of immune stimulation. These findings are consistent with early microglia activation observed in pre-manifest patients and indicate that mHTT gene expression affects microglia function in a cell-autonomous way.
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Affiliation(s)
- Nina Stöberl
- School of Biosciences, Cardiff University, Cardiff, UK.
| | - Jasmine Donaldson
- Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - Caroline S Binda
- Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - Branduff McAllister
- Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - Hazel Hall-Roberts
- UK Dementia Research Institute at Cardiff, Cardiff University, Cardiff, UK
| | - Lesley Jones
- Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - Thomas H Massey
- Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
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20
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Wilton DK, Mastro K, Heller MD, Gergits FW, Willing CR, Fahey JB, Frouin A, Daggett A, Gu X, Kim YA, Faull RLM, Jayadev S, Yednock T, Yang XW, Stevens B. Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington's disease. Nat Med 2023; 29:2866-2884. [PMID: 37814059 PMCID: PMC10667107 DOI: 10.1038/s41591-023-02566-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 08/24/2023] [Indexed: 10/11/2023]
Abstract
Huntington's disease (HD) is a devastating monogenic neurodegenerative disease characterized by early, selective pathology in the basal ganglia despite the ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to the development of early cognitive phenotypes are poorly understood. Here we show that there is selective loss of synaptic connections between the cortex and striatum in postmortem tissue from patients with HD that is associated with the increased activation and localization of complement proteins, innate immune molecules, to these synaptic elements. We also found that levels of these secreted innate immune molecules are elevated in the cerebrospinal fluid of premanifest HD patients and correlate with established measures of disease burden.In preclinical genetic models of HD, we show that complement proteins mediate the selective elimination of corticostriatal synapses at an early stage in disease pathogenesis, marking them for removal by microglia, the brain's resident macrophage population. This process requires mutant huntingtin to be expressed in both cortical and striatal neurons. Inhibition of this complement-dependent elimination mechanism through administration of a therapeutically relevant C1q function-blocking antibody or genetic ablation of a complement receptor on microglia prevented synapse loss, increased excitatory input to the striatum and rescued the early development of visual discrimination learning and cognitive flexibility deficits in these models. Together, our findings implicate microglia and the complement cascade in the selective, early degeneration of corticostriatal synapses and the development of cognitive deficits in presymptomatic HD; they also provide new preclinical data to support complement as a therapeutic target for early intervention.
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Affiliation(s)
- Daniel K Wilton
- F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, US.
| | - Kevin Mastro
- F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, US
| | - Molly D Heller
- F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, US
| | - Frederick W Gergits
- F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, US
| | - Carly Rose Willing
- F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, US
| | - Jaclyn B Fahey
- F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, US
| | - Arnaud Frouin
- F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, US
| | - Anthony Daggett
- Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
| | - Xiaofeng Gu
- Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
| | - Yejin A Kim
- F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, US
| | - Richard L M Faull
- Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Suman Jayadev
- Department of Neurology, University of Washington, Seattle, WA, USA
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Ted Yednock
- Annexon Biosciences, South San Francisco, CA, USA
| | - X William Yang
- Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
| | - Beth Stevens
- F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, US.
- Stanley Center, Broad Institute, Cambridge, MA, USA.
- Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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21
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Chen R, Routh BN, Gaudet AD, Fonken LK. Circadian Regulation of the Neuroimmune Environment Across the Lifespan: From Brain Development to Aging. J Biol Rhythms 2023; 38:419-446. [PMID: 37357738 PMCID: PMC10475217 DOI: 10.1177/07487304231178950] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
Circadian clocks confer 24-h periodicity to biological systems, to ultimately maximize energy efficiency and promote survival in a world with regular environmental light cycles. In mammals, circadian rhythms regulate myriad physiological functions, including the immune, endocrine, and central nervous systems. Within the central nervous system, specialized glial cells such as astrocytes and microglia survey and maintain the neuroimmune environment. The contributions of these neuroimmune cells to both homeostatic and pathogenic demands vary greatly across the day. Moreover, the function of these cells changes across the lifespan. In this review, we discuss circadian regulation of the neuroimmune environment across the lifespan, with a focus on microglia and astrocytes. Circadian rhythms emerge in early life concurrent with neuroimmune sculpting of brain circuits and wane late in life alongside increasing immunosenescence and neurodegeneration. Importantly, circadian dysregulation can alter immune function, which may contribute to susceptibility to neurodevelopmental and neurodegenerative diseases. In this review, we highlight circadian neuroimmune interactions across the lifespan and share evidence that circadian dysregulation within the neuroimmune system may be a critical component in human neurodevelopmental and neurodegenerative diseases.
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Affiliation(s)
- Ruizhuo Chen
- Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas
| | - Brandy N. Routh
- Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas
- Institute for Neuroscience, The University of Texas at Austin, Austin, Texas
| | - Andrew D. Gaudet
- Institute for Neuroscience, The University of Texas at Austin, Austin, Texas
- Department of Psychology, The University of Texas at Austin, Austin, Texas
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, Texas
| | - Laura K. Fonken
- Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas
- Institute for Neuroscience, The University of Texas at Austin, Austin, Texas
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22
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Gao C, Jiang J, Tan Y, Chen S. Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct Target Ther 2023; 8:359. [PMID: 37735487 PMCID: PMC10514343 DOI: 10.1038/s41392-023-01588-0] [Citation(s) in RCA: 294] [Impact Index Per Article: 147.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 07/11/2023] [Accepted: 08/03/2023] [Indexed: 09/23/2023] Open
Abstract
Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington's disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.
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Affiliation(s)
- Chao Gao
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Jingwen Jiang
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Yuyan Tan
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Shengdi Chen
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
- Lab for Translational Research of Neurodegenerative Diseases, Shanghai Institute for Advanced Immunochemical Studies (SIAIS), Shanghai Tech University, 201210, Shanghai, China.
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23
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Eide S, Misztal M, Feng ZP. Interleukin-6 as a marker of Huntington's disease progression: Systematic review and meta-analysis. Brain Behav Immun Health 2023; 30:100635. [PMID: 37215308 PMCID: PMC10196779 DOI: 10.1016/j.bbih.2023.100635] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 03/20/2023] [Accepted: 04/30/2023] [Indexed: 05/24/2023] Open
Abstract
Huntington's disease (HD) is a rare, inherited disorder with a broad spectrum of manifestations that vary with disease severity and progression. Although genetic testing can readily confirm the initial diagnosis of HD, markers sensitive to HD progression are needed to aid the development of individual treatment plans. The current analysis aims to identify plasma Interleukin-6 (IL-6) as a marker of disease progression in HD patients. A systematic search of PubMed and Medline from conception through October 2021 was conducted. Studies reporting plasma IL-6 levels of mutation-positive HD patients and healthy controls that met inclusion criteria were selected. The search strategy collected 303 studies, 9 of which met analysis inclusion criteria. From included studies, plasma IL-6 levels of 469 individuals with the HD mutation and 206 healthy controls were collected. Plasma IL-6 levels were meta-analytically compared between healthy controls and individuals with the confirmed HD mutation at all stages of disease and correlated to performance on standardized measures of total cognitive and motor function. Plasma IL-6 was significantly increased in HD groups compared to controls (g = 0.73, 95% CI = 0.31,1.16, P < 0.01) and increased significantly throughout most stages of disease progression, notably between pre-manifest and manifest (g = 0.31, 95% CI = 0.04,0.59, P < 0.05) and early and moderate HD stages (g = 0.52, 95% CI = 0.18,0.86, P < 0.01). Significant correlations between plasma IL-6 levels and HD symptomatic progression were identified, with increased cytokine levels associated with more severe motor impairments (r = 0.179, 95% CI = 0.0479,0.304, P = 0.008) and more extreme disabilities in activities of daily living and/or work tasks (r = -0.229, 95% CI = -0.334, -0.119, P < 0.001). Conclusively, plasma IL-6 levels correlate with disease and motor symptom progression and may act as a viable marker for clinical use. Analysis is limited by small study numbers and highlights the need for future work to identify definitive ranges or rates of change of plasma IL-6 levels that correlate to progressive HD disease states.
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Affiliation(s)
| | | | - Zhong-Ping Feng
- Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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24
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Gasser J, Gillet G, Valadas JS, Rouvière L, Kotian A, Fan W, Keaney J, Kadiu I. Innate immune activation and aberrant function in the R6/2 mouse model and Huntington's disease iPSC-derived microglia. Front Mol Neurosci 2023; 16:1191324. [PMID: 37415834 PMCID: PMC10319581 DOI: 10.3389/fnmol.2023.1191324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/24/2023] [Indexed: 07/08/2023] Open
Abstract
Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disease caused by CAG repeats in exon 1 of the HTT gene. A hallmark of HD along with other psychiatric and neurodegenerative diseases is alteration in the neuronal circuitry and synaptic loss. Microglia and peripheral innate immune activation have been reported in pre-symptomatic HD patients; however, what "activation" signifies for microglial and immune function in HD and how it impacts synaptic health remains unclear. In this study we sought to fill these gaps by capturing immune phenotypes and functional activation states of microglia and peripheral immunity in the R6/2 model of HD at pre-symptomatic, symptomatic and end stages of disease. These included characterizations of microglial phenotypes at single cell resolution, morphology, aberrant functions such as surveillance and phagocytosis and their impact on synaptic loss in vitro and ex vivo in R6/2 mouse brain tissue slices. To further understand how relevant the observed aberrant microglial behaviors are to human disease, transcriptomic analysis was performed using HD patient nuclear sequencing data and functional assessments were conducted using induced pluripotent stem cell (iPSC)-derived microglia. Our results show temporal changes in brain infiltration of peripheral lymphoid and myeloid cells, increases in microglial activation markers and phagocytic functions at the pre-symptomatic stages of disease. Increases in microglial surveillance and synaptic uptake parallel significant reduction of spine density in R6/2 mice. These findings were mirrored by an upregulation of gene signatures in the endocytic and migratory pathways in disease-associated microglial subsets in human HD brains, as well as increased phagocytic and migratory functions of iPSC-derived HD microglia. These results collectively suggest that targeting key and specific microglial functions related to synaptic surveillance and pruning may be therapeutically beneficial in attenuating cognitive decline and psychiatric aspects of HD.
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Affiliation(s)
- Julien Gasser
- Neuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, Belgium
| | - Gaelle Gillet
- Neuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, Belgium
| | - Jorge S. Valadas
- Neuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, Belgium
| | - Laura Rouvière
- Neuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, Belgium
| | - Apoorva Kotian
- Development Science, UCB Biopharma SRL, Slough, United Kingdom
| | - Wenqiang Fan
- Neuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, Belgium
| | - James Keaney
- Neuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, Belgium
| | - Irena Kadiu
- Neuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, Belgium
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25
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Khodaii J, Nomura Y, Chang NHS, Wong DF, Møller A, Gjedde A. Dopamine D 2/3 Receptor Availabilities in Striatal and Extrastriatal Regions of the Adult Human Brain: Comparison of Four Methods of Analysis. Neurochem Res 2023; 48:1517-1530. [PMID: 36525123 DOI: 10.1007/s11064-022-03825-4] [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: 08/21/2022] [Revised: 10/30/2022] [Accepted: 11/12/2022] [Indexed: 12/23/2022]
Abstract
Values of binding potentials (BPND) of dopamine D2/3 receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. We tested the claim that both striatal and extrastriatal dopamine D2/3 receptor availabilities vary with age in vivo in humans by determining the values of BPND of the specific radioligand [11C]raclopride. We determined values of BPND in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. We estimated values of BPND in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BPND in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four methods, including the ERLiBiRD (Estimation of Reversible Ligand Binding and Receptor Density) method, the tissue reference methods of Logan and Logan-Ichise, respectively, and the SRTM (Simplified Reference Tissue Method). Voxelwise generation of parametric maps of values of BPND used the multi-linear regression version of SRTM. Age-dependent changes of the binding potential presented with an inverted U-shape with peak binding potentials reached between the ages of 20 and 30. The estimates of BPND declined significantly with age after the peak in both striatal and extrastriatal regions, as determined by all four methods, with the greatest decline observed in posterior (occipital and parietal) cortices (14% per decade) and the lowest decline in caudate nucleus (3% per decade). The sites of the greatest declines are of particular interest because of the clinical implications.
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Affiliation(s)
- Javad Khodaii
- Department of Mechanical Engineering, Amirkabir University of Technology, Tehran, Iran
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yoshiyuki Nomura
- Department of Radiology, Faculty of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Natalie Hong Siu Chang
- Department of Clinical Research, University of Southern Denmark, 5000, Odense M, Denmark
| | - Dean F Wong
- Radiology, Psychiatry, Neurology and Neurosciences Washington University, St Louis, USA
| | - Arne Møller
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital, 8000, Aarhus, Denmark
- Center of Functionally Integrative Neuroscience, Aarhus University, 8000, Aarhus, Denmark
| | - Albert Gjedde
- Department of Clinical Research, University of Southern Denmark, 5000, Odense M, Denmark.
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8000, Aarhus C, Denmark.
- Department of Neuroscience, Panum Institute, University of Copenhagen, 3 Blegdamsvej, DK-2200, Copenhagen N, Denmark.
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada.
- Neuroscience Center, Tabriz University of Medical Sciences, Tabriz, 5166/15731, Iran.
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26
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Chen HL, Yang L, Zhang XLN, Jia QY, Duan ZD, Li JJ, Zheng LY, Liu TT, Qi Z, Yuan Y, Wu CY. Scutellarin Acts via MAPKs Pathway to Promote M2 Polarization of Microglial Cells. Mol Neurobiol 2023:10.1007/s12035-023-03338-3. [PMID: 37086342 DOI: 10.1007/s12035-023-03338-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 04/03/2023] [Indexed: 04/23/2023]
Abstract
Scutellarin, an herbal agent, is known to possess anti-oxidant and anti-inflammatory properties. In activated microglia, it has been reported that this is achieved through acting on the MAPKs, a key pathway that regulates microglia activation. This study sought to determine if scutellarin would affect the commonly described microglia phenotypes, namely, M1 and M2, thought to contribute to pro- and anti-inflammatory roles, respectively. This is in consideration of its potential effect on the polarization of microglia phenotypes that are featured prominently in cerebral ischemia. For this purpose, we have used an experimentally induced cerebral ischemia rat model and LPS-stimulated BV-2 cell model. Thus, by Western blot and immunofluorescence, we show here a noticeable increase in expression of M2 microglia markers, namely, CD206, Arg1, YM1/2, IL-4 and IL-10 in activated microglia both in vivo and in vitro. Besides, we have confirmed that Scutellarin upregulated expression of Arg1, IL-10 and IL-4 in medium supernatants of BV-2 microglia. Remarkably, scutellarin treatment markedly augmented the increased expression of the respective markers in activated microglia. It is therefore suggested scutellarin can exert the polarization of activated microglia from M1 to M2 phenotype. Because M1 microglia are commonly known to be proinflammatory, while M2 microglia are anti-inflammatory and neuroprotective effect, it stands to reason therefore that with the increase of M2 microglia which became predominant by scutellarin, the local inflammatory response is ameliorated. More importantly, we have found that scutellarin promotes the M2 polarization through inhibiting the JNK and p38 signaling pathways, and concomitantly augmenting the ERK1/2 signaling pathway. This lends its strong support from observations in LPS activated BV-2 microglia treated with p38 and JNK inhibitors in which expression of M2 markers was increased; on the other hand, in cells subjected to ERK1/2 inhibitor treatment, the expression was suppressed. In light of the above, MAPKs pathway is deemed to be a potential therapeutic target of scutellarin in mitigating microglia mediated neuroinflammation in activated microglia.
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Affiliation(s)
- Hao-Lun Chen
- Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China
| | - Li Yang
- Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China
| | - Xiao-Li-Na Zhang
- Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China
- Department of Pain Management, No.1 Affiliated Hospital, Kunming Medical University, 295 Xichang Road, Kunming, 650101, People's Republic of China
| | - Qiu-Ye Jia
- Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China
| | - Zhao-Da Duan
- Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China
| | - Juan-Juan Li
- Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China
| | - Li-Yang Zheng
- Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China
| | - Teng-Teng Liu
- Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China
| | - Zhi Qi
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China
- School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China
| | - Yun Yuan
- Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China.
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China.
| | - Chun-Yun Wu
- Department of Anatomy and Histology/Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People's Republic of China.
- Department of Neurology, No.2 Affiliated Hospital, Kunming Medical University, 374 Dianmian Road, Kunming, 650101, People's Republic of China.
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27
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Early TNF-Dependent Regulation of Excitatory and Inhibitory Synapses on Striatal Direct Pathway Medium Spiny Neurons in the YAC128 Mouse Model of Huntington's Disease. J Neurosci 2023; 43:672-680. [PMID: 36517241 PMCID: PMC9888503 DOI: 10.1523/jneurosci.1655-22.2022] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 12/07/2022] [Accepted: 12/11/2022] [Indexed: 12/15/2022] Open
Abstract
Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin gene. Neurodegeneration first occurs in the striatum, accompanied by an elevation in inflammatory cytokines. Using the presymptomatic male YAC128 HD model mouse, we examined the synaptic input onto the striatal medium spiny neurons to look for early changes that precede degeneration. We observed an increase in excitatory synaptic strength, as measured by AMPA/NMDA ratios, specifically on direct pathway D1 receptor expressing medium spiny neurons, with no changes on indirect pathway neurons. The changes in excitation were accompanied by a decrease in inhibitory synaptic strength, as measured by the amplitude of miniature inhibitory synaptic currents. The pro-inflammatory cytokine tumor necrosis factor alpha (TNF) was elevated in the striatum of YAC128 at the ages examined. Critically, the changes in excitatory and inhibitory inputs are both dependent on TNF signaling, as blocking TNF signaling genetically or pharmacological normalized synaptic strength. The observed changes in synaptic function are similar to the changes seen in D1 medium spiny neurons treated with high levels of TNF, suggesting that saturating levels of TNF exist in the striatum even at early stages of HD. The increase in glutamatergic synaptic strength and decrease in inhibitory synaptic strength would increase direct pathway neuronal excitability, which may potentiate excitotoxicity during the progress of HD.SIGNIFICANCE STATEMENT The striatum is the first structure to degenerate in Huntington's disease, but the early changes that presage the degeneration are not well defined. Here we identify early synaptic changes in the YAC128 mouse model of Huntington's disease specifically on a subpopulation of striatal neurons. These neurons have stronger excitatory synapses and weaker inhibitory inputs, and thus would increase the susceptibility to excitotoxicity. These changes are dependent on signaling by the pro-inflammatory cytokine TNFα. TNF is elevated even at early presymptomatic stages, and blocking TNF signaling even acutely will reverse the synaptic changes. This suggests early intervention could be important therapeutically.
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28
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Role of Nrf2 in aging, Alzheimer's and other neurodegenerative diseases. Ageing Res Rev 2022; 82:101756. [PMID: 36243357 DOI: 10.1016/j.arr.2022.101756] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 09/14/2022] [Accepted: 10/09/2022] [Indexed: 01/31/2023]
Abstract
Nuclear Factor-Erythroid Factor 2 (Nrf2) is an important transcription factor that regulates the expression of large number of genes in healthy and disease states. Nrf2 is made up of 605 amino acids and contains 7 conserved regions known as Nrf2-ECH homology domains. Nrf2 regulates the expression of several key components of oxidative stress, mitochondrial biogenesis, mitophagy, autophagy and mitochondrial function in all organs of the human body, in the peripheral and central nervous systems. Mounting evidence also suggests that altered expression of Nrf2 is largely involved in aging, neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's diseases, Amyotrophic lateral sclerosis, Stroke, Multiple sclerosis and others. The purpose of this article is to detail the essential role of Nrf2 in oxidative stress, antioxidative defense, detoxification, inflammatory responses, transcription factors, proteasomal and autophagic/mitophagic degradation, and metabolism in aging and neurodegenerative diseases. This article also highlights the Nrf2 structural and functional activities in healthy and disease states, and also discusses the current status of Nrf2 research and therapeutic strategies to treat aging and neurodegenerative diseases.
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29
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Bains M, Kaur J, Akhtar A, Kuhad A, Sah SP. Anti-inflammatory effects of ellagic acid and vanillic acid against quinolinic acid-induced rat model of Huntington's disease by targeting IKK-NF-κB pathway. Eur J Pharmacol 2022; 934:175316. [DOI: 10.1016/j.ejphar.2022.175316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 09/19/2022] [Accepted: 09/30/2022] [Indexed: 11/26/2022]
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30
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de Oliveira Furlam T, Roque IG, Machado da Silva EW, Vianna PP, Costa Valadão PA, Guatimosim C, Teixeira AL, de Miranda AS. Inflammasome activation and assembly in Huntington's disease. Mol Immunol 2022; 151:134-142. [PMID: 36126501 DOI: 10.1016/j.molimm.2022.09.002] [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: 05/16/2022] [Revised: 08/24/2022] [Accepted: 09/04/2022] [Indexed: 11/16/2022]
Abstract
Huntington's disease (HD) is a rare neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Inflammasomes are multiprotein complexes capable of sensing pathogen-associated and damage-associated molecular patterns, triggering innate immune pathways. Activation of inflammasomes results in a pro-inflammatory cascade involving, among other molecules, caspases and interleukins. NLRP3 (nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3) is the most studied inflammasome complex, and its activation results in caspase-1 mediated cleavage of the pro-interleukins IL-1β and IL-18 into their mature forms, also inducing a gasdermin D mediated form of pro-inflammatory cell death, i.e. pyroptosis. Accumulating evidence has implicated NLRP3 inflammasome complex in neurodegenerative diseases. The evidence in HD is still scant and mostly derived from pre-clinical studies. This review aims to present the available evidence on NLRP3 inflammasome activation in HD and to discuss whether targeting this innate immune system complex might be a promising therapeutic strategy to alleviate its symptoms.
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Affiliation(s)
| | | | | | - Pedro Parenti Vianna
- School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Cristina Guatimosim
- Department of Morphology - Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Antônio Lúcio Teixeira
- Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA; Faculdade Santa Casa BH, Belo Horizonte, MG, Brazil
| | - Aline Silva de Miranda
- Department of Morphology - Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
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31
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Tabrizi SJ, Estevez-Fraga C, van Roon-Mom WMC, Flower MD, Scahill RI, Wild EJ, Muñoz-Sanjuan I, Sampaio C, Rosser AE, Leavitt BR. Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities. Lancet Neurol 2022; 21:645-658. [PMID: 35716694 PMCID: PMC7613206 DOI: 10.1016/s1474-4422(22)00121-1] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 02/18/2022] [Accepted: 03/04/2022] [Indexed: 01/03/2023]
Abstract
Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.
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Affiliation(s)
- Sarah J Tabrizi
- Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.
| | - Carlos Estevez-Fraga
- Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK
| | | | - Michael D Flower
- Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK
| | - Rachael I Scahill
- Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK
| | - Edward J Wild
- Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK
| | | | - Cristina Sampaio
- CHDI Management, CHDI Foundation Los Angeles, CA, USA; Laboratory of Clinical Pharmacology, Faculdade de Medicina de Lisboa, Lisbon, Portugal
| | - Anne E Rosser
- BRAIN unit, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - Blair R Leavitt
- Centre for Huntington's disease, University of British Columbia, Vancouver, BC, Canada
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Ortinski PI, Reissner KJ, Turner J, Anderson TA, Scimemi A. Control of complex behavior by astrocytes and microglia. Neurosci Biobehav Rev 2022; 137:104651. [PMID: 35367512 PMCID: PMC9119927 DOI: 10.1016/j.neubiorev.2022.104651] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/28/2022] [Accepted: 03/21/2022] [Indexed: 02/07/2023]
Abstract
Evidence that glial cells influence behavior has been gaining a steady foothold in scientific literature. Out of the five main subtypes of glial cells in the brain, astrocytes and microglia have received an outsized share of attention with regard to shaping a wide spectrum of behavioral phenomena and there is growing appreciation that the signals intrinsic to these cells as well as their interactions with surrounding neurons reflect behavioral history in a brain region-specific manner. Considerable regional diversity of glial cell phenotypes is beginning to be recognized and may contribute to behavioral outcomes arising from circuit-specific computations within and across discrete brain nuclei. Here, we summarize current knowledge on the impact of astrocyte and microglia activity on behavioral outcomes, with a specific focus on brain areas relevant to higher cognitive control, reward-seeking, and circadian regulation.
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Affiliation(s)
- P I Ortinski
- Department of Neuroscience, University of Kentucky, USA
| | - K J Reissner
- Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, USA
| | - J Turner
- Department of Pharmaceutical Sciences, University of Kentucky, USA
| | - T A Anderson
- Department of Neuroscience, University of Kentucky, USA
| | - A Scimemi
- Department of Biology, State University of New York at Albany, USA
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Saba J, Couselo FL, Bruno J, Carniglia L, Durand D, Lasaga M, Caruso C. Neuroinflammation in Huntington's Disease: A Starring Role for Astrocyte and Microglia. Curr Neuropharmacol 2022; 20:1116-1143. [PMID: 34852742 PMCID: PMC9886821 DOI: 10.2174/1570159x19666211201094608] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/06/2021] [Accepted: 11/26/2021] [Indexed: 11/22/2022] Open
Abstract
Huntington's disease (HD) is a neurodegenerative genetic disorder caused by a CAG repeat expansion in the huntingtin gene. HD causes motor, cognitive, and behavioral dysfunction. Since no existing treatment affects the course of this disease, new treatments are needed. Inflammation is frequently observed in HD patients before symptom onset. Neuroinflammation, characterized by the presence of reactive microglia, astrocytes and inflammatory factors within the brain, is also detected early. However, in comparison to other neurodegenerative diseases, the role of neuroinflammation in HD is much less known. Work has been dedicated to altered microglial and astrocytic functions in the context of HD, but less attention has been given to glial participation in neuroinflammation. This review describes evidence of inflammation in HD patients and animal models. It also discusses recent knowledge on neuroinflammation in HD, highlighting astrocyte and microglia involvement in the disease and considering anti-inflammatory therapeutic approaches.
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Affiliation(s)
- Julieta Saba
- Instituto de Investigaciones Biomédicas (INBIOMED), UBA-CONICET, Paraguay 2155, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Federico López Couselo
- Instituto de Investigaciones Biomédicas (INBIOMED), UBA-CONICET, Paraguay 2155, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Julieta Bruno
- Instituto de Investigaciones Biomédicas (INBIOMED), UBA-CONICET, Paraguay 2155, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Lila Carniglia
- Instituto de Investigaciones Biomédicas (INBIOMED), UBA-CONICET, Paraguay 2155, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Daniela Durand
- Instituto de Investigaciones Biomédicas (INBIOMED), UBA-CONICET, Paraguay 2155, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Mercedes Lasaga
- Instituto de Investigaciones Biomédicas (INBIOMED), UBA-CONICET, Paraguay 2155, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carla Caruso
- Instituto de Investigaciones Biomédicas (INBIOMED), UBA-CONICET, Paraguay 2155, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina,Address correspondence to this author at the Instituto de Investigaciones Biomédicas (INBIOMED), UBA-CONICET, Paraguay 2155 Piso 10, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina, Tel: +54 11 5285 3380; E-mail:
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Kacher R, Mounier C, Caboche J, Betuing S. Altered Cholesterol Homeostasis in Huntington’s Disease. Front Aging Neurosci 2022; 14:797220. [PMID: 35517051 PMCID: PMC9063567 DOI: 10.3389/fnagi.2022.797220] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 03/18/2022] [Indexed: 12/25/2022] Open
Abstract
Huntington’s disease (HD) is an autosomal dominant genetic disorder caused by an expansion of the CAG repeat in the first exon of Huntingtin’s gene. The associated neurodegeneration mainly affects the striatum and the cortex at early stages and progressively spreads to other brain structures. Targeting HD at its earlier stages is under intense investigation. Numerous drugs were tested, with a rate of success of only 3.5% approved molecules used as symptomatic treatment. The restoration of cholesterol metabolism, which is central to the brain homeostasis and strongly altered in HD, could be an interesting disease-modifying strategy. Cholesterol is an essential membrane component in the central nervous system (CNS); alterations of its homeostasis have deleterious consequences on neuronal functions. The levels of several sterols, upstream of cholesterol, are markedly decreased within the striatum of HD mouse model. Transcription of cholesterol biosynthetic genes is reduced in HD cell and mouse models as well as post-mortem striatal and cortical tissues from HD patients. Since the dynamic of brain cholesterol metabolism is complex, it is essential to establish the best method to target it in HD. Cholesterol, which does not cross the blood-brain-barrier, is locally synthesized and renewed within the brain. All cell types in the CNS synthesize cholesterol during development but as they progress through adulthood, neurons down-regulate their cholesterol synthesis and turn to astrocytes for their full supply. Cellular levels of cholesterol reflect the dynamic balance between synthesis, uptake and export, all integrated into the context of the cross talk between neurons and glial cells. In this review, we describe the latest advances regarding the role of cholesterol deregulation in neuronal functions and how this could be a determinant factor in neuronal degeneration and HD progression. The pathways and major mechanisms by which cholesterol and sterols are regulated in the CNS will be described. From this overview, we discuss the main clinical strategies for manipulating cholesterol metabolism in the CNS, and how to reinstate a proper balance in HD.
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Affiliation(s)
- Radhia Kacher
- Institut du Cerveau - Paris Brain Institute (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Sorbonne Université, Paris, France
- INSERM, U1216, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France
| | - Coline Mounier
- Neuroscience Paris Seine, Institut de Biologie Paris-Seine, Faculté des Sciences et Ingénierie, Sorbonne Université, Paris, France
- Centre National de la Recherche Scientifique, UMR 8246, Paris, France
- U1130, Institut National de la Santé et de la Recherche Médicale, Paris, France
| | - Jocelyne Caboche
- Neuroscience Paris Seine, Institut de Biologie Paris-Seine, Faculté des Sciences et Ingénierie, Sorbonne Université, Paris, France
- Centre National de la Recherche Scientifique, UMR 8246, Paris, France
- U1130, Institut National de la Santé et de la Recherche Médicale, Paris, France
| | - Sandrine Betuing
- Neuroscience Paris Seine, Institut de Biologie Paris-Seine, Faculté des Sciences et Ingénierie, Sorbonne Université, Paris, France
- Centre National de la Recherche Scientifique, UMR 8246, Paris, France
- U1130, Institut National de la Santé et de la Recherche Médicale, Paris, France
- *Correspondence: Sandrine Betuing,
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Chen K, Lai C, Su Y, Bao WD, Yang LN, Xu PP, Zhu LQ. cGAS-STING-mediated IFN-I response in host defense and neuro-inflammatory diseases. Curr Neuropharmacol 2021; 20:362-371. [PMID: 34561985 PMCID: PMC9413793 DOI: 10.2174/1570159x19666210924110144] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 08/06/2021] [Accepted: 08/10/2021] [Indexed: 11/22/2022] Open
Abstract
The presence of foreign or misplaced nucleic acids is a danger signal that triggers innate immune responses through activating cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and binding to its downstream signaling effector stimulator of interferon genes (STING). Then the cGAS-STING pathway activation links nucleic acid sensing to immune responses and pathogenic entities clearance. However, overactivation of this signaling pathway leads to fatal immune disorders and contributes to the progression of many human inflammatory diseases. Therefore, optimal activation of this pathway is crucial for the elimination of invading pathogens and the maintenance of immune homeostasis. In this review, we will summarize its fundamental roles in initiating host defense against invading pathogens and discuss its pathogenic roles in multiple neuro-inflammatory diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and other neurodegenerative diseases.
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Affiliation(s)
- Kai Chen
- Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chuan Lai
- Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yin Su
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wen Dai Bao
- Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Liu Nan Yang
- Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ping-Ping Xu
- Endoscopy Center, Wuhan Children's Hospital , Tongji Medical College, Huazhong University of Science and Technology, China
| | - Ling-Qiang Zhu
- Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Soni N, Ora M, Bathla G, Nagaraj C, Boles Ponto LL, Graham MM, Saini J, Menda Y. Multiparametric magnetic resonance imaging and positron emission tomography findings in neurodegenerative diseases: Current status and future directions. Neuroradiol J 2021; 34:263-288. [PMID: 33666110 PMCID: PMC8447818 DOI: 10.1177/1971400921998968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Neurodegenerative diseases (NDDs) are characterized by progressive neuronal loss, leading to dementia and movement disorders. NDDs broadly include Alzheimer's disease, frontotemporal lobar degeneration, parkinsonian syndromes, and prion diseases. There is an ever-increasing prevalence of mild cognitive impairment and dementia, with an accompanying immense economic impact, prompting efforts aimed at early identification and effective interventions. Neuroimaging is an essential tool for the early diagnosis of NDDs in both clinical and research settings. Structural, functional, and metabolic imaging modalities, including magnetic resonance imaging (MRI) and positron emission tomography (PET), are widely available. They show encouraging results for diagnosis, monitoring, and treatment response evaluation. The current review focuses on the complementary role of various imaging modalities in relation to NDDs, the qualitative and quantitative utility of newer MRI techniques, novel radiopharmaceuticals, and integrated PET/MRI in the setting of NDDs.
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Affiliation(s)
- Neetu Soni
- University of Iowa Hospitals and Clinics, USA
| | - Manish Ora
- Department of Nuclear Medicine, SGPGIMS, India
| | - Girish Bathla
- Neuroradiology Department, University of Iowa Hospitals and
Clinics, USA
| | - Chandana Nagaraj
- Department of Neuro Imaging and Interventional Radiology,
NIMHANS, India
| | | | - Michael M Graham
- Division of Nuclear Medicine, University of Iowa Hospitals and
Clinics, USA
| | - Jitender Saini
- Department of Neuro Imaging and Interventional Radiology,
NIMHANS, India
| | - Yusuf Menda
- University of Iowa Hospitals and Clinics, USA
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Benraiss A, Mariani JN, Osipovitch M, Cornwell A, Windrem MS, Villanueva CB, Chandler-Militello D, Goldman SA. Cell-intrinsic glial pathology is conserved across human and murine models of Huntington's disease. Cell Rep 2021; 36:109308. [PMID: 34233199 DOI: 10.1016/j.celrep.2021.109308] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 02/22/2021] [Accepted: 06/04/2021] [Indexed: 12/15/2022] Open
Abstract
Glial pathology is a causal contributor to the striatal neuronal dysfunction of Huntington's disease (HD). We investigate mutant HTT-associated changes in gene expression by mouse and human striatal astrocytes, as well as in mouse microglia, to identify commonalities in glial pathobiology across species and models. Mouse striatal astrocytes are fluorescence-activated cell sorted (FACS) from R6/2 and zQ175 mice, which respectively express exon1-only or full-length mHTT, and human astrocytes are generated either from human embryonic stem cells (hESCs) expressing full-length mHTT or from fetal striatal astrocytes transduced with exon1-only mHTT. Comparison of differential gene expression across these conditions, all with respect to normal HTT controls, reveals cell-type-specific changes in transcription common to both species, yet with differences that distinguish glia expressing truncated mHTT versus full-length mHTT. These data indicate that the differential gene expression of glia expressing truncated mHTT may differ from that of cells expressing full-length mHTT, while identifying a conserved set of dysregulated pathways in HD glia.
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Affiliation(s)
- Abdellatif Benraiss
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
| | - John N Mariani
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Mikhail Osipovitch
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Translational Neuromedicine, University of Copenhagen Faculty of Health, Copenhagen 2200, Denmark
| | - Adam Cornwell
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Martha S Windrem
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Carlos Benitez Villanueva
- Center for Translational Neuromedicine, University of Copenhagen Faculty of Health, Copenhagen 2200, Denmark
| | - Devin Chandler-Militello
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Translational Neuromedicine, University of Copenhagen Faculty of Health, Copenhagen 2200, Denmark; Neuroscience Center, Rigshospitalet-Copenhagen University Hospital, Copenhagen, Denmark.
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Pogoda A, Chmielewska N, Maciejak P, Szyndler J. Transcriptional Dysregulation in Huntington's Disease: The Role in Pathogenesis and Potency for Pharmacological Targeting. Curr Med Chem 2021; 28:2783-2806. [PMID: 32628586 DOI: 10.2174/0929867327666200705225821] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/15/2020] [Accepted: 06/19/2020] [Indexed: 11/22/2022]
Abstract
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the gene that encodes a critical cell regulatory protein, huntingtin (Htt). The expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats causes improper folding of functional proteins and is an initial trigger of pathological changes in the brain. Recent research has indicated that the functional dysregulation of many transcription factors underlies the neurodegenerative processes that accompany HD. These disturbances are caused not only by the loss of wild-type Htt (WT Htt) function but also by the occurrence of abnormalities that result from the action of mutant Htt (mHtt). In this review, we aim to describe the role of transcription factors that are currently thought to be strongly associated with HD pathogenesis, namely, RE1-silencing transcription factor, also known as neuron-restrictive silencer factor (REST/NRSF), forkhead box proteins (FOXPs), peroxisome proliferator-activated receptor gamma coactivator-1a (PGC1α), heat shock transcription factor 1 (HSF1), and nuclear factor κ light-chain-enhancer of activated B cells (NF- κB). We also take into account the role of these factors in the phenotype of HD as well as potential pharmacological interventions targeting the analyzed proteins. Furthermore, we considered whether molecular manipulation resulting in changes in transcription factor function may have clinical potency for treating HD.
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Affiliation(s)
- Aleksandra Pogoda
- Faculty of Medicine, Medical University of Warsaw, Zwirki i Wigury Street 61, 02-097 Warsaw, Poland
| | - Natalia Chmielewska
- Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957 Warsaw, Poland
| | - Piotr Maciejak
- Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957 Warsaw, Poland
| | - Janusz Szyndler
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Banacha Street 1B, 02-097 Warsaw, Poland
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Rocha NP, Charron O, Latham LB, Colpo GD, Zanotti-Fregonara P, Yu M, Freeman L, Furr Stimming E, Teixeira AL. Microglia Activation in Basal Ganglia Is a Late Event in Huntington Disease Pathophysiology. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2021; 8:e984. [PMID: 33795375 PMCID: PMC8017723 DOI: 10.1212/nxi.0000000000000984] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 01/20/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To define the role played by microglia in different stages of Huntington disease (HD), we used the TSPO radioligand [11C]-ER176 and PET to evaluate microglial activation in relation to neurodegeneration and in relation to the clinical features seen at premanifest and manifest stages of the disease. METHODS This is a cross-sectional study in which 18 subjects (6 controls, 6 premanifest, and 6 manifest HD gene carriers) underwent a [11C]-ER176 PET scan and an MRI for anatomic localization. Segmentation of regions of interest (ROIs) was performed, and group differences in [11C]-ER176 binding (used to evaluate the extent of microglial activation) were assessed by the standardized uptake value ratio (SUVR). Microglial activation was correlated with ROIs volumes, disease burden, and the scores obtained in the clinical scales. As an exploratory aim, we evaluated the dynamic functions of microglia in vitro, by using induced microglia-like (iMG) cells from peripheral blood monocytes. RESULTS Individuals with manifest HD present higher [11C]-ER176 SUVR in both globi pallidi and putamina in comparison with controls. No differences were observed when we compared premanifest HD with controls or with manifest HD. We also found a significant correlation between increased microglial activation and cumulative disease burden, and with reduced volumes. iMG from controls, premanifest HD, and manifest HD patients showed similar phagocytic capacity. CONCLUSIONS Altogether, our data demonstrate that microglial activation is involved in HD pathophysiology and is associated with disease progression.
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Affiliation(s)
- Natalia P. Rocha
- From the Mitchell Center for Alzheimer's Disease and Related Brain Disorders (N.P.R.), Department of Neurology, McGovern Medical School, The University of Texas Health Science Center, Houston; Department of Neurology (O.C., L.F.), The University of Texas at Austin; School of Medicine (L.B.L.), University of Washington, Seattle; Neuropsychiatry Program (G.D.C., A.L.T.), Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas, Houston; Houston Methodist Research Institute and Weill Cornell Medicine (P.Z.-F., M.Y.), TX; and HDSA Center of Excellence at University of Texas Health Science Center at Houston (E.F.S.)
| | - Odelin Charron
- From the Mitchell Center for Alzheimer's Disease and Related Brain Disorders (N.P.R.), Department of Neurology, McGovern Medical School, The University of Texas Health Science Center, Houston; Department of Neurology (O.C., L.F.), The University of Texas at Austin; School of Medicine (L.B.L.), University of Washington, Seattle; Neuropsychiatry Program (G.D.C., A.L.T.), Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas, Houston; Houston Methodist Research Institute and Weill Cornell Medicine (P.Z.-F., M.Y.), TX; and HDSA Center of Excellence at University of Texas Health Science Center at Houston (E.F.S.)
| | - Leigh B. Latham
- From the Mitchell Center for Alzheimer's Disease and Related Brain Disorders (N.P.R.), Department of Neurology, McGovern Medical School, The University of Texas Health Science Center, Houston; Department of Neurology (O.C., L.F.), The University of Texas at Austin; School of Medicine (L.B.L.), University of Washington, Seattle; Neuropsychiatry Program (G.D.C., A.L.T.), Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas, Houston; Houston Methodist Research Institute and Weill Cornell Medicine (P.Z.-F., M.Y.), TX; and HDSA Center of Excellence at University of Texas Health Science Center at Houston (E.F.S.)
| | - Gabriela D. Colpo
- From the Mitchell Center for Alzheimer's Disease and Related Brain Disorders (N.P.R.), Department of Neurology, McGovern Medical School, The University of Texas Health Science Center, Houston; Department of Neurology (O.C., L.F.), The University of Texas at Austin; School of Medicine (L.B.L.), University of Washington, Seattle; Neuropsychiatry Program (G.D.C., A.L.T.), Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas, Houston; Houston Methodist Research Institute and Weill Cornell Medicine (P.Z.-F., M.Y.), TX; and HDSA Center of Excellence at University of Texas Health Science Center at Houston (E.F.S.)
| | - Paolo Zanotti-Fregonara
- From the Mitchell Center for Alzheimer's Disease and Related Brain Disorders (N.P.R.), Department of Neurology, McGovern Medical School, The University of Texas Health Science Center, Houston; Department of Neurology (O.C., L.F.), The University of Texas at Austin; School of Medicine (L.B.L.), University of Washington, Seattle; Neuropsychiatry Program (G.D.C., A.L.T.), Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas, Houston; Houston Methodist Research Institute and Weill Cornell Medicine (P.Z.-F., M.Y.), TX; and HDSA Center of Excellence at University of Texas Health Science Center at Houston (E.F.S.)
| | - Meixiang Yu
- From the Mitchell Center for Alzheimer's Disease and Related Brain Disorders (N.P.R.), Department of Neurology, McGovern Medical School, The University of Texas Health Science Center, Houston; Department of Neurology (O.C., L.F.), The University of Texas at Austin; School of Medicine (L.B.L.), University of Washington, Seattle; Neuropsychiatry Program (G.D.C., A.L.T.), Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas, Houston; Houston Methodist Research Institute and Weill Cornell Medicine (P.Z.-F., M.Y.), TX; and HDSA Center of Excellence at University of Texas Health Science Center at Houston (E.F.S.)
| | - Leorah Freeman
- From the Mitchell Center for Alzheimer's Disease and Related Brain Disorders (N.P.R.), Department of Neurology, McGovern Medical School, The University of Texas Health Science Center, Houston; Department of Neurology (O.C., L.F.), The University of Texas at Austin; School of Medicine (L.B.L.), University of Washington, Seattle; Neuropsychiatry Program (G.D.C., A.L.T.), Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas, Houston; Houston Methodist Research Institute and Weill Cornell Medicine (P.Z.-F., M.Y.), TX; and HDSA Center of Excellence at University of Texas Health Science Center at Houston (E.F.S.)
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Wanrooy BJ, Wen SW, Wong CH. Dynamic roles of neutrophils in post-stroke neuroinflammation. Immunol Cell Biol 2021; 99:924-935. [PMID: 33894069 DOI: 10.1111/imcb.12463] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/12/2021] [Accepted: 04/20/2021] [Indexed: 01/03/2023]
Abstract
Clinical trials involving the blockage of peripheral inflammatory leukocyte recruitment into the brain have puzzlingly led to either no significant improvement in stroke outcome, or even worsened outcomes and increased mortality, prompting a re-evaluation of our understanding into the neuroinflammatory processes after stroke. Whilst traditionally understood as simple effectors of the innate immune system, emerging research in vascular disease biology has redefined the neutrophil as a specialized and highly specific cell type with dynamic functional capacity. Indeed, emerging experimental evidence indicates that neutrophils display diverse roles in the acute stages of ischemic stroke with the ability to elicit both pro-inflammatory and anti-inflammatory effects. Currently, there is some uncertainty as to whether neutrophil diversity is beneficial or harmful in stroke as their interactions with the resident cells of the brain, such as microglia and neurons, would potentially elicit heterogeneous outcomes. Current treatments for patients with stroke aim to remove the vascular blockage and to restore blood flow, but there are currently no drug treatments for managing the loss of functional brain tissue nor restoration of microglial and neuronal damage. If these hypothesized wound-healing functions of neutrophils can be validated in a stroke setting, promoting the recruitment of this type of neutrophils into the injured brain tissue may form a promising therapeutic target for the majority of stroke patients currently without treatment. In this review, we will provide an update on recent research that has explored neutrophil heterogeneity in the neuroinflammatory cascade after ischemic stroke.
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Affiliation(s)
- Brooke J Wanrooy
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
| | - Shu Wen Wen
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
| | - Connie Hy Wong
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
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41
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O'Regan GC, Farag SH, Casey CS, Wood-Kaczmar A, Pocock JM, Tabrizi SJ, Andre R. Human Huntington's disease pluripotent stem cell-derived microglia develop normally but are abnormally hyper-reactive and release elevated levels of reactive oxygen species. J Neuroinflammation 2021; 18:94. [PMID: 33874957 PMCID: PMC8054367 DOI: 10.1186/s12974-021-02147-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 04/01/2021] [Indexed: 01/13/2023] Open
Abstract
Background Neuroinflammation may contribute to the pathogenesis of Huntington’s disease, given evidence of activated microglia and elevated levels of inflammatory molecules in disease gene carriers, even those many years from symptom onset. We have shown previously that monocytes from Huntington’s disease patients are hyper-reactive to stimulation in a manner dependent on their autonomous expression of the disease-causing mutant HTT protein. To date, however, whether human microglia are similarly hyper-responsive in a cell-autonomous manner has not been determined. Methods Microglial-like cells were derived from human pluripotent stem cells (PSCs) expressing mutant HTT containing varying polyglutamine lengths. These included lines that are otherwise isogenic, such that any observed differences can be attributed with certainty to the disease mutation itself. Analyses by quantitative PCR and immunofluorescence microscopy respectively of key genes and protein markers were undertaken to determine whether Huntington’s disease PSCs differentiated normally to a microglial fate. The resultant cultures and their supernatants were then assessed by various biochemical assays and multiplex ELISAs for viability and responses to stimulation, including the release of pro-inflammatory cytokines and reactive oxygen species. Conditioned media were applied to PSC-derived striatal neurons, and vice versa, to determine the effects that the secretomes of each cell type might have on the other. Results Human PSCs generated microglia successfully irrespective of the expression of mutant HTT. These cells, however, were hyper-reactive to stimulation in the production of pro-inflammatory cytokines such as IL-6 and TNFα. They also released elevated levels of reactive oxygen species that have neurotoxic potential. Accompanying such phenotypes, human Huntington’s disease PSC-derived microglia showed increased levels of apoptosis and were more susceptible to exogenous stress. Such stress appeared to be induced by supernatants from human PSC-derived striatal neurons expressing mutant HTT with a long polyglutamine tract. Conclusions These studies show, for the first time, that human Huntington’s disease PSC-derived microglia are hyper-reactive due to their autonomous expression of mutant HTT. This provides a cellular basis for the contribution that neuroinflammation might make to Huntington’s disease pathogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02147-6.
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Affiliation(s)
- Grace C O'Regan
- Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK
| | - Sahar H Farag
- Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK
| | - Caroline S Casey
- Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK
| | - Alison Wood-Kaczmar
- Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK
| | - Jennifer M Pocock
- Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College London, WC1N 1PJ, London, UK
| | - Sarah J Tabrizi
- Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK.
| | - Ralph Andre
- Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG, London, UK.
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Etxeberria-Rekalde E, Alzola-Aldamizetxebarria S, Flunkert S, Hable I, Daurer M, Neddens J, Hutter-Paier B. Quantification of Huntington's Disease Related Markers in the R6/2 Mouse Model. Front Mol Neurosci 2021; 13:617229. [PMID: 33505246 PMCID: PMC7831778 DOI: 10.3389/fnmol.2020.617229] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/10/2020] [Indexed: 12/12/2022] Open
Abstract
Huntington’s disease (HD) is caused by an expansion of CAG triplets in the huntingtin gene, leading to severe neuropathological changes that result in a devasting and lethal phenotype. Neurodegeneration in HD begins in the striatum and spreads to other brain regions such as cortex and hippocampus, causing motor and cognitive dysfunctions. To understand the signaling pathways involved in HD, animal models that mimic the human pathology are used. The R6/2 mouse as model of HD was already shown to present major neuropathological changes in the caudate putamen and other brain regions, but recently established biomarkers in HD patients were yet not analyzed in these mice. We therefore performed an in-depth analysis of R6/2 mice to establish new and highly translational readouts focusing on Ctip2 as biological marker for motor system-related neurons and translocator protein (TSPO) as a promising readout for early neuroinflammation. Our results validate already shown pathologies like mutant huntingtin aggregates, ubiquitination, and brain atrophy, but also provide evidence for decreased tyrosine hydroxylase and Ctip2 levels as indicators of a disturbed motor system, while vesicular acetyl choline transporter levels as marker for the cholinergic system barely change. Additionally, increased astrocytosis and activated microglia were observed by GFAP, Iba1 and TSPO labeling, illustrating, that TSPO is a more sensitive marker for early neuroinflammation compared to GFAP and Iba1. Our results thus demonstrate a high sensitivity and translational value of Ctip2 and TSPO as new marker for the preclinical evaluation of new compounds in the R6/2 mouse model of HD.
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Affiliation(s)
| | | | | | - Isabella Hable
- QPS Austria GmbH, Grambach, Austria.,Department of Health Studies, FH Joanneum University of Applied Sciences, Graz, Austria
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43
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van Wamelen DJ, Aziz NA. Hypothalamic pathology in Huntington disease. HANDBOOK OF CLINICAL NEUROLOGY 2021; 182:245-255. [PMID: 34266596 DOI: 10.1016/b978-0-12-819973-2.00017-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Huntington's disease (HD), an autosomal dominant hereditary disorder associated with the accumulation of mutant huntingtin, is classically associated with cognitive decline and motor symptoms, notably chorea. However, growing evidence suggests that nonmotor symptoms are equally prevalent and debilitating. Some of these symptoms may be linked to hypothalamic pathology, demonstrated by findings in HD animal models and HD patients showing specific changes in hypothalamic neuropeptidergic populations and their associated functions. At least some of these alterations are likely due to local mutant huntingtin expression and toxicity, while others are likely caused by disturbed hypothalamic circuitry. Common problems include circadian rhythm disorders, including desynchronization of daily hormone excretion patterns, which could be targeted by novel therapeutic interventions, such as timed circadian interventions with light therapy or melatonin. However, translation of these findings from bench-to-bedside is hampered by differences in murine HD models and HD patients, including mutant huntingtin trinucleotide repeat length, which is highly heterogeneous across the various models. In this chapter, we summarize the current knowledge regarding hypothalamic alterations in HD patients and animal models, and the potential for these findings to be translated into clinical practice and management.
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Affiliation(s)
- Daniel J van Wamelen
- Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Parkinson's Foundation Centre of Excellence, King's College Hospital, London, United Kingdom; Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
| | - N Ahmad Aziz
- Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Neurology, Faculty of Medicine, University of Bonn, Bonn, Germany
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44
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O'Regan GC, Farag SH, Ostroff GR, Tabrizi SJ, Andre R. Wild-type huntingtin regulates human macrophage function. Sci Rep 2020; 10:17269. [PMID: 33057179 PMCID: PMC7560844 DOI: 10.1038/s41598-020-74042-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 09/17/2020] [Indexed: 01/07/2023] Open
Abstract
The huntingtin (HTT) protein in its mutant form is the cause of the inherited neurodegenerative disorder, Huntington's disease. Beyond its effects in the central nervous system, disease-associated mutant HTT causes aberrant phenotypes in myeloid-lineage innate immune system cells, namely monocytes and macrophages. Whether the wild-type form of the protein, however, has a role in normal human macrophage function has not been determined. Here, the effects of lowering the expression of wild-type (wt)HTT on the function of primary monocyte-derived macrophages from healthy, non-disease human subjects were examined. This demonstrated a previously undescribed role for wtHTT in maintaining normal macrophage health and function. Lowered wtHTT expression was associated, for instance, with a diminished release of induced cytokines, elevated phagocytosis and increased vulnerability to cellular stress. These may well occur by mechanisms different to that associated with the mutant form of the protein, given an absence of any effect on the intracellular signalling pathway predominantly associated with macrophage dysfunction in Huntington's disease.
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Affiliation(s)
- Grace C O'Regan
- UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Sahar H Farag
- UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Gary R Ostroff
- Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Two Biotech, Suite 113, Worcester, MA, 01605, USA
| | - Sarah J Tabrizi
- UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK. .,UK Dementia Research Institute at UCL, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
| | - Ralph Andre
- UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
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45
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Karalija N, Jonassson L, Johansson J, Papenberg G, Salami A, Andersson M, Riklund K, Nyberg L, Boraxbekk CJ. High long-term test-retest reliability for extrastriatal 11C-raclopride binding in healthy older adults. J Cereb Blood Flow Metab 2020; 40:1859-1868. [PMID: 31506011 PMCID: PMC7446562 DOI: 10.1177/0271678x19874770] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In vivo dopamine D2-receptor availability is frequently assessed with 11C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for 11C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal 11C-raclopride binding potential (BPND) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test-retest reliability in a sample of younger adults. The present work demonstrates high seven-month test-retest reliability of striatal and extrastriatal 11C-raclopride BPND values in healthy, older adults (n = 27, age: 64-78 years). Mean 11C-raclopride BPND values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85-0.96), absolute variability was low (mean: 4-8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional 11C-raclopride BPND values correlated with previously determined 18F-fallypride BPND values (ρ = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: ρ = 0.92; p < 0.001; excluding striatum: ρ = 0.75; p = 0.067). These observations suggest that extrastriatal 11C-raclopride measurements represent a true D2 signal.
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Affiliation(s)
- Nina Karalija
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
| | - Lars Jonassson
- Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Jarkko Johansson
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
| | - Goran Papenberg
- Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden
| | - Alireza Salami
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.,Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.,Wallenberg Centre for Molecular Medicine, Lund, Sweden
| | - Micael Andersson
- Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Katrine Riklund
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
| | - Lars Nyberg
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Carl-Johan Boraxbekk
- Department of Radiation Sciences, Umeå University, Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.,Danish Research Center for Magnetic Resonance, Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark
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46
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Crapser JD, Ochaba J, Soni N, Reidling JC, Thompson LM, Green KN. Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease. Brain 2020; 143:266-288. [PMID: 31848580 DOI: 10.1093/brain/awz363] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 08/22/2019] [Accepted: 10/01/2019] [Indexed: 12/12/2022] Open
Abstract
Huntington's disease is associated with a reactive microglial response and consequent inflammation. To address the role of these cells in disease pathogenesis, we depleted microglia from R6/2 mice, a rapidly progressing model of Huntington's disease marked by behavioural impairment, mutant huntingtin (mHTT) accumulation, and early death, through colony-stimulating factor 1 receptor inhibition (CSF1Ri) with pexidartinib (PLX3397) for the duration of disease. Although we observed an interferon gene signature in addition to downregulated neuritogenic and synaptic gene pathways with disease, overt inflammation was not evident by microglial morphology or cytokine transcript levels in R6/2 mice. Nonetheless, CSF1Ri-induced microglial elimination reduced or prevented disease-related grip strength and object recognition deficits, mHTT accumulation, astrogliosis, and striatal volume loss, the latter of which was not associated with reductions in cell number but with the extracellular accumulation of chondroitin sulphate proteoglycans (CSPGs)-a primary component of glial scars. A concurrent loss of proteoglycan-containing perineuronal nets was also evident in R6/2 mice, and microglial elimination not only prevented this but also strikingly increased perineuronal nets in the brains of naïve littermates, suggesting a new role for microglia as homeostatic regulators of perineuronal net formation and integrity.
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Affiliation(s)
- Joshua D Crapser
- Department of Neurobiology and Behavior, University of California, Irvine (UCI), Irvine, CA, USA.,Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA
| | - Joseph Ochaba
- Department of Neurobiology and Behavior, University of California, Irvine (UCI), Irvine, CA, USA.,Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA
| | - Neelakshi Soni
- Department of Neurobiology and Behavior, University of California, Irvine (UCI), Irvine, CA, USA.,Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA
| | - Jack C Reidling
- Department of Neurobiology and Behavior, University of California, Irvine (UCI), Irvine, CA, USA.,Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA
| | - Leslie M Thompson
- Department of Neurobiology and Behavior, University of California, Irvine (UCI), Irvine, CA, USA.,Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.,Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA
| | - Kim N Green
- Department of Neurobiology and Behavior, University of California, Irvine (UCI), Irvine, CA, USA.,Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA
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47
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Cheong RY, Gabery S, Petersén Å. The Role of Hypothalamic Pathology for Non-Motor Features of Huntington's Disease. J Huntingtons Dis 2020; 8:375-391. [PMID: 31594240 PMCID: PMC6839491 DOI: 10.3233/jhd-190372] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Huntington’s disease (HD) is a fatal genetic neurodegenerative disorder. It has mainly been considered a movement disorder with cognitive symptoms and these features have been associated with pathology of the striatum and cerebral cortex. Importantly, individuals with the mutant huntingtin gene suffer from a spectrum of non-motor features often decades before the motor disorder manifests. These symptoms and signs include a range of psychiatric symptoms, sleep problems and metabolic changes with weight loss particularly in later stages. A higher body mass index at diagnosis is associated with slower disease progression. The common psychiatric symptom of apathy progresses with the disease. The fact that non-motor features are present early in the disease and that they show an association to disease progression suggest that unravelling the underlying neurobiological mechanisms may uncover novel targets for early disease intervention and better symptomatic treatment. The hypothalamus and the limbic system are important brain regions that regulate emotion, social cognition, sleep and metabolism. A number of studies using neuroimaging, postmortem human tissue and genetic manipulation in animal models of the disease has collectively shown that the hypothalamus and the limbic system are affected in HD. These findings include the loss of neuropeptide-expressing neurons such as orexin (hypocretin), oxytocin, vasopressin, somatostatin and VIP, and increased levels of SIRT1 in distinct nuclei of the hypothalamus. This review provides a summary of the results obtained so far and highlights the potential importance of these changes for the understanding of non-motor features in HD.
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Affiliation(s)
- Rachel Y Cheong
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Sanaz Gabery
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Åsa Petersén
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
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48
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Wilton DK, Stevens B. The contribution of glial cells to Huntington's disease pathogenesis. Neurobiol Dis 2020; 143:104963. [PMID: 32593752 DOI: 10.1016/j.nbd.2020.104963] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 05/07/2020] [Accepted: 06/10/2020] [Indexed: 12/20/2022] Open
Abstract
Glial cells play critical roles in the normal development and function of neural circuits, but in many neurodegenerative diseases, they become dysregulated and may contribute to the development of brain pathology. In Huntington's disease (HD), glial cells both lose normal functions and gain neuropathic phenotypes. In addition, cell-autonomous dysfunction elicited by mutant huntingtin (mHTT) expression in specific glial cell types is sufficient to induce both pathology and Huntington's disease-related impairments in motor and cognitive performance, suggesting that these cells may drive the development of certain aspects of Huntington's disease pathogenesis. In support of this imaging studies in pre-symptomatic HD patients and work on mouse models have suggested that glial cell dysfunction occurs at a very early stage of the disease, prior to the onset of motor and cognitive deficits. Furthermore, selectively ablating mHTT from specific glial cells or correcting for HD-induced changes in their transcriptional profile rescues some HD-related phenotypes, demonstrating the potential of targeting these cells for therapeutic intervention. Here we review emerging research focused on understanding the involvement of different glial cell types in specific aspects of HD pathogenesis. This work is providing new insight into how HD impacts biological functions of glial cells in the healthy brain as well as how HD induced dysfunction in these cells might change the way they integrate into biological circuits.
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Affiliation(s)
- Daniel K Wilton
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Beth Stevens
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Stanley Center, Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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49
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Cybulska K, Perk L, Booij J, Laverman P, Rijpkema M. Huntington's Disease: A Review of the Known PET Imaging Biomarkers and Targeting Radiotracers. Molecules 2020; 25:molecules25030482. [PMID: 31979301 PMCID: PMC7038198 DOI: 10.3390/molecules25030482] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/14/2020] [Accepted: 01/15/2020] [Indexed: 12/19/2022] Open
Abstract
Huntington’s disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the huntingtin gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomography (PET) studies relating to HD was performed, including clinical and preclinical data. PET is a powerful tool for visualisation of the HD pathology by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed molecular snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognise particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochemical picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.
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Affiliation(s)
- Klaudia Cybulska
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 EZ Nijmegen, The Netherlands; (J.B.); (P.L.); (M.R.)
- Radboud Translational Medicine B.V., Radboud University Medical Center, Geert Grooteplein 21 (route 142), 6525 EZ Nijmegen, The Netherlands;
- Correspondence:
| | - Lars Perk
- Radboud Translational Medicine B.V., Radboud University Medical Center, Geert Grooteplein 21 (route 142), 6525 EZ Nijmegen, The Netherlands;
| | - Jan Booij
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 EZ Nijmegen, The Netherlands; (J.B.); (P.L.); (M.R.)
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Peter Laverman
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 EZ Nijmegen, The Netherlands; (J.B.); (P.L.); (M.R.)
| | - Mark Rijpkema
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 EZ Nijmegen, The Netherlands; (J.B.); (P.L.); (M.R.)
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50
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Brandes MS, Gray NE. NRF2 as a Therapeutic Target in Neurodegenerative Diseases. ASN Neuro 2020; 12:1759091419899782. [PMID: 31964153 PMCID: PMC6977098 DOI: 10.1177/1759091419899782] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 11/26/2019] [Accepted: 12/03/2019] [Indexed: 12/13/2022] Open
Abstract
Increased reactive oxygen species production and oxidative stress have been implicated in the pathogenesis of numerous neurodegenerative conditions including among others Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Friedrich’s ataxia, multiple sclerosis, and stroke. The endogenous antioxidant response pathway protects cells from oxidative stress by increasing the expression of cytoprotective enzymes and is regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). In addition to regulating the expression of antioxidant genes, NRF2 has also been shown to exert anti-inflammatory effects and modulate both mitochondrial function and biogenesis. This is because mitochondrial dysfunction and neuroinflammation are features of many neurodegenerative diseases as well NRF2 has emerged as a promising therapeutic target. Here, we review evidence for a beneficial role of NRF2 in neurodegenerative conditions and the potential of specific NRF2 activators as therapeutic agents.
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Affiliation(s)
- Mikah S. Brandes
- Department of Neurology, Oregon Health and Science University, Portland, OR, USA
| | - Nora E. Gray
- Department of Neurology, Oregon Health and Science University, Portland, OR, USA
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