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Fraile-Ramos J, Dogoh F, Ogiator M, Oghagbon EK, Giménez-Llort L. Cognitive impairment and blood biomarkers of renal dysfunction in high-risk Nigerian population, with special attention to women and diabetes. BMC Neurol 2025; 25:158. [PMID: 40217181 PMCID: PMC11987182 DOI: 10.1186/s12883-025-04173-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND Sub-Saharan Africans and Afro-Americans face 2-to-8 times higher risk of dementia compared to Caucasians, with Nigerian people being the highest population-at-risk. Adding to this challenge, their unique lipid profile increases their susceptibility to type 2 diabetes mellitus (DM-2), which further raises the risk of cognitive impairment (CI) by 1.5 times. Recently, we demonstrated a strong Diabetes/Dementia tandem in Nigerians, with increased cognitive vulnerability in illiterate, short-height, and diabetic Nigerian women in the eye of the storm. The combination of factors within this population makes it the optimal scenario to understand the relationship between CI and DM-2. METHODS Here, we further studied the blood biochemical analysis of our Makurdi cohort and searched for correlations with standard anthropometric measures, educational level, cognitive status (as assessed with MMSE, 6-CIT) and DM-2. RESULTS CI was prevalent across all groups, with higher incidence in DM-2 subjects and a marked sexual dimorphism. Thus, women exhibited a greater risk, especially those with low educational attainment. In the search for potential blood-based biomarkers for cognitive function, we identified those related to renal function. In particular, elevated uric acid and urea levels were associated with poorer cognitive performance, highlighting a potential kidney-brain axis connection. CONCLUSION Renal function blood metabolites in this Nigerian cohort have been identified as possible kidney-brain axis biomarkers of CI. Moreover, illiteracy, female sex, and DM-2 pose them a compounded risk of developing CI. These findings advocate that targeted interventions addressing educational disparities and metabolic health could be proposed to mitigate cognitive decline in these vulnerable sub-groups. The integration of these factors provides a comprehensive understanding of CI incidence in Nigeria's population, offering new avenues for diagnosis, prevention, and treatment strategies. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Juan Fraile-Ramos
- Department of Psychiatry and Forensic Medicine, School of Medicine, Universitat Autònoma de Barcelona, Avinguda Can Domènec, s/n, Cerdanyola del Vallès, Barcelona, 08193, Spain
- Institut de Neurociències, Universitat Autònoma de Barcelona, Carrer de la Vinya, s/n, Cerdanyola del Vallès, Barcelona, 08193, Spain
| | - Faeren Dogoh
- Department of Chemical Pathology, Benue State University Teaching Hospital, Gboko Road, Makurdi, 970101, Nigeria
| | - Monday Ogiator
- Department of Internal Medicine, Benue State University Teaching Hospital, Gboko Road, Makurdi, 970101, Nigeria
| | - Efosa Kenneth Oghagbon
- Department of Chemical Pathology, Benue State University Teaching Hospital, Gboko Road, Makurdi, 970101, Nigeria.
- Department of Chemical Pathology, Faculty of Basic & Allied Medical Sciences, College of Health Sciences, Benue State University, Gboko Road, Makurdi, 970101, Nigeria.
| | - Lydia Giménez-Llort
- Department of Psychiatry and Forensic Medicine, School of Medicine, Universitat Autònoma de Barcelona, Avinguda Can Domènec, s/n, Cerdanyola del Vallès, Barcelona, 08193, Spain.
- Institut de Neurociències, Universitat Autònoma de Barcelona, Carrer de la Vinya, s/n, Cerdanyola del Vallès, Barcelona, 08193, Spain.
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Alsaleem MA, Al‐Kuraishy HM, Al‐Gareeb AI, Abdel‐Fattah MM, Alrouji M, Al‐Harchan NA, Alruwaili M, Papadakis M, Alexiou A, Batiha GE. Decrypting the Possible Mechanistic Role of Fenofibrate in Alzheimer's Disease and Type 2 Diabetes: The Truth and Mystery. J Cell Mol Med 2025; 29:e70378. [PMID: 40040308 PMCID: PMC11880132 DOI: 10.1111/jcmm.70378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/18/2024] [Accepted: 01/15/2025] [Indexed: 03/06/2025] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease caused by the progressive deposition of extracellular amyloid beta (Aβ) and intracellular neurofibrillary tangles (NFTs). Of note, metabolic disorders such as insulin resistance (IR) and type 2 diabetes (T2D) are associated with the development of brain IR and associated neurodegeneration. In addition, AD neuropathology and linked cognitive impairment accelerate the development of peripheral IR and the progression of T2D. Therefore, there is a bidirectional relationship between T2D and AD. It has been demonstrated that AD and T2D induce dysregulation of peroxisome proliferator-activated receptor alpha (PPAR-α) leading to the central and peripheral metabolic disturbances. Hence, dysregulated PPAR-α could be a shared mechanism in both AD and T2D, and restoration of PPAR-α signalling by PPAR-α agonist fenofibrate (FN) may alleviate T2D and AD. Therefore, this review aims to shed light on the potential involvement of PPAR-α in T2D and AD, and how FN could be effective in the management of AD. FN seems to be effective in both AD and T2D by dual neuroprotective and antidiabetic effects that can mitigate AD neuropathology and T2D-related complications by modulating various cellular processes and inflammatory signalling pathways. In conclusion, FN could be a possible candidate in the management of AD and T2D by modulating different signalling pathways involved in the pathogenesis of these conditions.
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Affiliation(s)
- Mansour A. Alsaleem
- Unit of Scientific Research, Applied CollegeQassim UniversityBuraydahSaudi Arabia
| | - Hayder M. Al‐Kuraishy
- Department of Clinical Pharmacology and Medicine, College of MedicineMustansiriyah UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical PharmacologyJabir Ibn Hayyan Medical UniversityKufaIraq
| | - Maha M. Abdel‐Fattah
- Department of Pharmacology and Toxicology, Faculty of PharmacyBeni‐Suef UniversityBeni‐SuefEgypt
| | - Mohammed Alrouji
- Department of Clinical Laboratory Sciences, College of Applied Medical SciencesShaqra UniversityShaqraSaudi Arabia
| | - Nasser A. Al‐Harchan
- Department of Clinical Pharmacology, College of DentistryAl‐Rasheed UniversityBaghdadIraq
| | - Mubarak Alruwaili
- Department of Internal Medicine, College of MedicineJouf UniversitySakakaSaudi Arabia
| | - Marios Papadakis
- University Hospital Witten‐HerdeckeUniversity of Witten‐HerdeckeWuppertalGermany
| | - Athanasios Alexiou
- University Centre for Research & DevelopmentChandigarh UniversityMohaliIndia
- Department of Science and EngineeringNovel Global Community Educational FoundationSydneyNew South WalesAustralia
- Department of Research & DevelopmentFunogenAthensGreece
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhour UniversityDamanhour, AlBeheiraEgypt
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Dustin CM, Shiva SS, Vazquez A, Saeed A, Pascoal T, Cifuentes-Pagano E, Pagano PJ. NOX2 in Alzheimer's and Parkinson's disease. Redox Biol 2024; 78:103433. [PMID: 39616884 PMCID: PMC11647642 DOI: 10.1016/j.redox.2024.103433] [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: 07/26/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 12/11/2024] Open
Abstract
Alzheimer's Disease (AD), and related dementias, represent a growing concern for the worldwide population given the increased numbers of people of advanced age. Marked by significant degradation of neurological tissues and critical processes, in addition to more specific factors such as the presence of amyloid plaques and neurofibrillary tangles in AD, robust discussion is ongoing regarding the precise mechanisms by which these diseases arise. One of the major interests in recent years has been the contribution of reactive oxygen species (ROS) and, particularly, the contribution of the ROS-generating NADPH Oxidase proteins. NADPH Oxidase 2 (NOX2), the prototypical member of the family, represents a particularly interesting target for study given its close association with vascular and inflammatory processes in all tissues, including the brain, and the association of these processes with AD development and progression. In this review, we discuss the most relevant and recent work regarding the contribution of NOX2 to AD progression in neuronal, microglial, and cerebrovascular signaling. Furthermore, we will discuss the most promising NOX2-targeted therapeutics for potential AD management and treatment.
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Affiliation(s)
- Christopher M Dustin
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Sruti S Shiva
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Alberto Vazquez
- Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 1526, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, 1526, USA
| | - Anum Saeed
- Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Tharick Pascoal
- Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Eugenia Cifuentes-Pagano
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Patrick J Pagano
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
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El-Hakim Y, Mani KK, Pickle KA, Akbari Z, Samiya N, Pham C, Salas G, Pilla R, Sohrabji F. Peripheral, but not central, IGF-1 treatment attenuates stroke-induced cognitive impairment in middle-aged female Sprague Dawley rats: The gut as a therapeutic target. Brain Behav Immun 2024; 122:150-166. [PMID: 39142422 PMCID: PMC11972691 DOI: 10.1016/j.bbi.2024.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 07/18/2024] [Accepted: 08/08/2024] [Indexed: 08/16/2024] Open
Abstract
Stroke results in immediate sensory or motor disability and increases the risk for long term cognitive-affective impairments. Thus, therapies are urgently needed to improve quality of life for stroke survivors, especially women who are at a greater risk for severe stroke after menopause. Most current research on stroke therapies target the central nervous system; however, stroke also impacts peripheral organ systems. Our studies using acyclic (estrogen-deficient) middle aged female Sprague Dawley rats show that this group not only displays worse outcomes after stroke as compared to adult females, but also has lower levels of the neuroprotective peptide Insulin-like Growth Factor (IGF1) in circulation. Intracerebroventricular (ICV) administration of IGF1 to this group decreases infarct volume and improves sensory motor performance in the acute phase. In this study, we show that, despite this neuroprotection, ICV-IGF1 did not reduce peripheral inflammation or improve post stroke cognitive impairment in the chronic phase. In view of the evidence that stroke induces rapid gut dysfunction, we tested whether systemic delivery of IGF1 (intraperitoneal, IP) would promote gut health and consequently improve long-term behavioral outcomes. Surprisingly, while IP-IGF1, delivered 4 h and 24 h after ischemic stroke, did not reduce infarct volume or acute sensory motor impairment, it significantly attenuated circulating levels of pro-inflammatory cytokines, and attenuated stroke-induced cognitive impairment. In addition, IP-IGF1 treatment reduced gut dysmorphology and gut dysbiosis. Our data support the conclusion that therapeutics targeting peripheral targets are critical for long-term stroke recovery, and that gut repair is a novel therapeutic target to improve brain health in aging females.
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Affiliation(s)
- Yumna El-Hakim
- Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-Health Science Center, Bryan TX-77807 USA
| | - Kathiresh Kumar Mani
- Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-Health Science Center, Bryan TX-77807 USA
| | - Kaylin A Pickle
- Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-Health Science Center, Bryan TX-77807 USA
| | - Zara Akbari
- Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-Health Science Center, Bryan TX-77807 USA
| | - Nadia Samiya
- Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-Health Science Center, Bryan TX-77807 USA
| | - Chloe Pham
- Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-Health Science Center, Bryan TX-77807 USA
| | - Gianna Salas
- Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-Health Science Center, Bryan TX-77807 USA
| | - Rachel Pilla
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine Texas A&M University, College Station, TX Brazos
| | - Farida Sohrabji
- Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-Health Science Center, Bryan TX-77807 USA.
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Nuber-Champier A, Breville G, Voruz P, Jacot de Alcântara I, Cionca A, Allali G, Lalive PH, Benzakour L, Lövblad KO, Braillard O, Nehme M, Coen M, Serratrice J, Reny JL, Pugin J, Guessous I, Landis BN, Assal F, Péron JA. Systemic cytokines related to memory function 6-9 months and 12-15 months after SARS-CoV-2 infection. Sci Rep 2024; 14:22660. [PMID: 39349924 PMCID: PMC11443073 DOI: 10.1038/s41598-024-72421-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 09/06/2024] [Indexed: 10/04/2024] Open
Abstract
Cognitive symptoms persisting beyond the acute phase of COVID-19 infection are commonly described for up to 2 years after infection. The relationship between cognitive performance, in particular episodic memory processes observed chronically after infection, and cytokine levels in the acute phase of COVID-19 has not yet been identified in humans. To determine whether the levels of cytokines IL1β, IL-6 and TNFα secreted in the acute phase of SARS-CoV-2 infection are associated and predict verbal and visuospatial episodic memory performance in humans 6 to 9 months and 12 to 15 months post-infection. The associations and predictive value of the concentration of cytokines measured in acute phase (IL-1β, IL-6, TNFα) from plasma samples of N = 33 hospitalized COVID-19 patients (mean age 61 years, 39-78, 65% in intensive care) in relation to their verbal and visuospatial episodic memory performance measured at 6-9 months and 12-15 months post-infection were analyzed. To do this, we used Spearman correlations and generalised linear mixed models. IL-1β levels were associated with verbal episodic memory total recall scores 6-9 months post-infection. At 12-15 months post-infection IL-6 predicted verbal episodic memory score. This study demonstrated that the severity of inflammatory reaction at acute phase of SARS-CoV-2 infection predicts verbal episodic memory performance in the long-term post-infection.
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Affiliation(s)
- A Nuber-Champier
- Clinical and Experimental Neuropsychology Laboratory, Faculté de Psychologie et Des Sciences de l'Education, University of Geneva, 40 bd du Pont d'Arve, 1205, Geneva, Switzerland
- Neurology Division, Geneva University Hospitals, Geneva, Switzerland
| | - G Breville
- Neurology Division, Geneva University Hospitals, Geneva, Switzerland
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
| | - P Voruz
- Clinical and Experimental Neuropsychology Laboratory, Faculté de Psychologie et Des Sciences de l'Education, University of Geneva, 40 bd du Pont d'Arve, 1205, Geneva, Switzerland
- Neurosurgery Department, Geneva University Hospitals, Geneva, Switzerland
| | - I Jacot de Alcântara
- Clinical and Experimental Neuropsychology Laboratory, Faculté de Psychologie et Des Sciences de l'Education, University of Geneva, 40 bd du Pont d'Arve, 1205, Geneva, Switzerland
- Neurology Division, Geneva University Hospitals, Geneva, Switzerland
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - A Cionca
- Clinical and Experimental Neuropsychology Laboratory, Faculté de Psychologie et Des Sciences de l'Education, University of Geneva, 40 bd du Pont d'Arve, 1205, Geneva, Switzerland
| | - G Allali
- Leenaards Memory Center, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - P H Lalive
- Neurology Division, Geneva University Hospitals, Geneva, Switzerland
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - L Benzakour
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Psychiatry Department, Geneva University Hospitals, Geneva, Switzerland
| | - K-O Lövblad
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Diagnostic and Interventional Neuroradiology Department, Geneva University Hospitals, Geneva, Switzerland
| | - O Braillard
- Division and Department of Primary Care, Geneva University Hospitals, Geneva, Switzerland
| | - M Nehme
- Division and Department of Primary Care, Geneva University Hospitals, Geneva, Switzerland
| | - M Coen
- Division of General Internal Medicine, Department of Medicine, Geneva University Hospitals and Geneva University, Geneva, Switzerland
| | - J Serratrice
- Division of General Internal Medicine, Department of Medicine, Geneva University Hospitals and Geneva University, Geneva, Switzerland
| | - J-L Reny
- Division of General Internal Medicine, Department of Medicine, Geneva University Hospitals and Geneva University, Geneva, Switzerland
| | - J Pugin
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Intensive Care Department, Geneva University Hospitals, Geneva, Switzerland
| | - I Guessous
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Division and Department of Primary Care, Geneva University Hospitals, Geneva, Switzerland
| | - B N Landis
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Rhinology-Olfactology Unit, Otorhinolaryngology Department, Geneva University Hospitals, Geneva, Switzerland
| | - F Assal
- Neurology Division, Geneva University Hospitals, Geneva, Switzerland
- Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Julie Anne Péron
- Clinical and Experimental Neuropsychology Laboratory, Faculté de Psychologie et Des Sciences de l'Education, University of Geneva, 40 bd du Pont d'Arve, 1205, Geneva, Switzerland.
- Neurology Division, Geneva University Hospitals, Geneva, Switzerland.
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Doroszkiewicz J, Mroczko J, Winkel I, Mroczko B. Metabolic and Immune System Dysregulation: Unraveling the Connections between Alzheimer's Disease, Diabetes, Inflammatory Bowel Diseases, and Rheumatoid Arthritis. J Clin Med 2024; 13:5057. [PMID: 39274269 PMCID: PMC11396443 DOI: 10.3390/jcm13175057] [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: 08/09/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/16/2024] Open
Abstract
Alzheimer's disease (AD), diabetes mellitus (DM), inflammatory bowel diseases (IBD), and rheumatoid arthritis (RA) are chronic conditions affecting millions globally. Despite differing clinical symptoms, these diseases share pathophysiological mechanisms involving metabolic and immune system dysregulation. This paper examines the intricate connections between these disorders, focusing on shared pathways such as insulin resistance, lipid metabolism dysregulation, oxidative stress, and chronic inflammation. An important aspect is the role of amyloid-beta plaques and tau protein tangles, which are hallmark features of AD. These protein aggregates are influenced by metabolic dysfunction and inflammatory processes similar to those seen in DM, RA, and IBD. This manuscript explores how amyloid and tau pathologies may be exacerbated by shared metabolic and immune dysfunction. Additionally, this work discusses the gut-brain axis and the influence of gut microbiota in mediating disease interactions. Understanding these commonalities opens new avenues for multi-targeted therapeutic approaches that address the root causes rather than merely the symptoms of these conditions. This integrative perspective could lead to more effective interventions and improved patient outcomes, emphasizing the importance of a unified approach in managing these interconnected diseases.
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Affiliation(s)
- Julia Doroszkiewicz
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
| | - Jan Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
| | - Izabela Winkel
- Dementia Disorders Centre, Medical University of Wroclaw, 50-425 Scinawa, Poland
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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Ceprián N, Martínez de Toda I, Maté I, Garrido A, Gimenez-Llort L, De la Fuente M. Prodromic Inflammatory-Oxidative Stress in Peritoneal Leukocytes of Triple-Transgenic Mice for Alzheimer's Disease. Int J Mol Sci 2024; 25:6976. [PMID: 39000092 PMCID: PMC11241217 DOI: 10.3390/ijms25136976] [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: 05/17/2024] [Revised: 06/24/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Inflammatory-oxidative stress is known to be pivotal in the pathobiology of Alzheimer's disease (AD), but the involvement of this stress at the peripheral level in the disease's onset has been scarcely studied. This study investigated the pro-inflammatory profile and oxidative stress parameters in peritoneal leukocytes from female triple-transgenic mice for AD (3xTgAD) and non-transgenic mice (NTg). Peritoneal leukocytes were obtained at 2, 4, 6, 12, and 15 months of age. The concentrations of TNFα, INFγ, IL-1β, IL-2, IL-6, IL-17, and IL-10 released in cultures without stimuli and mitogen concanavalin A and lipopolysaccharide presence were measured. The concentrations of reduced glutathione (GSH), oxidized glutathione (GSSG), lipid peroxidation, and Hsp70 were also analyzed in the peritoneal cells. Our results showed that although there was a lower release of pro-inflammatory cytokines by 3xTgAD mice, this response was uncontrolled and overstimulated, especially at a prodromal stage at 2 months of age. In addition, there were lower concentrations of GSH in leukocytes from 3xTgAD and higher amounts of lipid peroxides at 2 and 4 months, as well as, at 6 months, a lower concentration of Hsp70. In conclusion, 3xTgAD mice show a worse pro-inflammatory response and higher oxidative stress than NTg mice during the prodromal stages, potentially supporting the idea that Alzheimer's disease could be a consequence of peripheral alteration in the leukocyte inflammation-oxidation state.
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Affiliation(s)
- Noemí Ceprián
- Animal Physiology Unit, Department of Genetics, Physiology and Microbiology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain
- Institute of Investigation Hospital 12 Octubre (imas12), 28041 Madrid, Spain
| | - Irene Martínez de Toda
- Animal Physiology Unit, Department of Genetics, Physiology and Microbiology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain
- Institute of Investigation Hospital 12 Octubre (imas12), 28041 Madrid, Spain
| | - Ianire Maté
- Department of Immunology, Microbiology and Parasitology, Faculty of Pharmacy, University of the Basque Country, 01006 Vitoria-Gasteiz, Spain
| | - Antonio Garrido
- Department of Biosciences, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, 28670 Madrid, Spain
| | - Lydia Gimenez-Llort
- Department of Psychiatry and Forensic Medicine, Institute of Neuroscience, School of Medicine, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain
| | - Mónica De la Fuente
- Animal Physiology Unit, Department of Genetics, Physiology and Microbiology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain
- Institute of Investigation Hospital 12 Octubre (imas12), 28041 Madrid, Spain
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de Aquino AMI, Gomes KAL, de Brito LLM, de Lima LD, Gomes ERDM, Andrade SMMDS. Diagnostic accuracy of interleukin-6, interleukin-10 and tumor necrosis factor alpha cytokine levels in patients with mild cognitive impairment: systematic review and meta-analysis. Dement Neuropsychol 2024; 18:e20230027. [PMID: 38933077 PMCID: PMC11206232 DOI: 10.1590/1980-5764-dn-2023-0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 03/07/2024] [Accepted: 03/12/2024] [Indexed: 06/28/2024] Open
Abstract
There is growing evidence suggesting an association between neurodegeneration and inflammation playing a role in the pathogenesis of age-associated diseases, including Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). Objective A systematic review and meta-analysis were performed to verify evidence on the diagnostic accuracy parameters of the inflammatory cytokines interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α). Methods A search of Medical Literature Analysis and Retrieval System Online (Medline), Scientific Electronic Library Online (SciELO), Web of Science and Science Direct databases was performed and nine observational studies associated with peripheral inflammatory biomarkers in MCI were identified. Mean (±standard deviation - SD) concentrations of these biomarkers and values of true positives, true negatives, false positives and false negatives for MCI and healthy controls (HC) were extracted from these studies. Results Significantly higher levels of IL-10 were observed in subjects in the MCI group and Mini-Mental State Examination (MMSE) scores were lower compared to HC. For the other investigations, no differences were found between the groups. Our meta-analysis for the TNF-α biomarker revealed high heterogeneity between studies in terms of sensitivity and specificity. Conclusion These findings do not support the involvement of inflammatory biomarkers for detection of MCI, although significant heterogeneity was observed. More studies are needed to evaluate the role of these cytokines in MCI, as well as in other stages of cognitive decline and all-cause dementias.
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Affiliation(s)
- Alana Mara Inácio de Aquino
- Universidade Federal da Paraíba, Laboratório de Envelhecimento e Neurociências, João Pessoa PB, Brazil
- Universidade Federal da Paraíba, Programa de Graduação em Neurociências e Comportamento, João Pessoa PB, Brazil
| | - Kedma Anne Lima Gomes
- Universidade Federal da Paraíba, Laboratório de Envelhecimento e Neurociências, João Pessoa PB, Brazil
- Universidade Federal da Paraíba, Programa de Graduação em Neurociências e Comportamento, João Pessoa PB, Brazil
| | | | - Luciana Domingos de Lima
- Universidade Federal da Paraíba, Laboratório de Envelhecimento e Neurociências, João Pessoa PB, Brazil
- Universidade Federal da Paraíba, Graduação em Fisioterapia, João Pessoa PB, Brazil
| | - Eneas Ricardo de Morais Gomes
- Universidade Federal da Paraíba, Cento de Biotecnologia, Departamento de Biotecnolgia, João Pessoa PB, Brazil
- Universidade Federal da Paraíba, Graduação em Biotecnologia, João Pessoa PB, Brazil
| | - Suellen Mary Marinho dos Santos Andrade
- Universidade Federal da Paraíba, Laboratório de Envelhecimento e Neurociências, João Pessoa PB, Brazil
- Universidade Federal da Paraíba, Programa de Graduação em Neurociências e Comportamento, João Pessoa PB, Brazil
- Universidade Federal da Paraíba, Departamento de Fisioterapia, João Pessoa PB, Brazil
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Khatri A, Prakash O, Agarwal R, Kushwaha S. Systemic inflammatory markers and their association with Alzheimer's disease: A cross-sectional analysis. Indian J Psychiatry 2024; 66:287-292. [PMID: 39100114 PMCID: PMC11293294 DOI: 10.4103/indianjpsychiatry.indianjpsychiatry_975_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/30/2024] [Accepted: 02/13/2024] [Indexed: 08/06/2024] Open
Abstract
Aim To investigate the possible role of systemic inflammatory markers (interleukin; IL-6, C-reactive protein; CRP, and albumin levels) in the development of Alzheimer's dementia (AD) and also find their association with the severity of disease. Material and Methods It was a cross-sectional study. Patients with Alzheimer's dementia (AD) and vascular dementia (VaD) from outpatient settings in tertiary care hospitals and non-demented controls (NDC) were recruited from the community. Individuals aged 50 years and older (n = 110) were included. Serum levels of IL-6, CRP, and albumin levels in patients with AD, VaD, and NDC were measured. The clinical Dementia Rating Scale was used for staging the severity of dementia. Serum levels of IL-6, CRP, and serum albumin were compared in study subjects and also analyzed with the severity of dementia in dementia subgroups. Results Our main finding was that serum levels of IL-6 were significantly elevated in patients with AD and VaD (7.79 and 6.60) as compared to NDC (2.98) (P < 0.001). No significant difference in CRP or albumin levels was observed between the three groups. Serum IL-6 and CRP showed a positive correlation with the severity of AD, though the correlation was significant only for IL-6 (r = 0.777). The serum albumin levels showed a statistically significant negative correlation with the severity of AD (r > 0.3 but <0.5). Conclusion The study demonstrates a notable association between systemic inflammatory markers, particularly IL-6, and the severity of AD, indicating their potential role in its pathogenesis. These findings suggest that targeting these markers could offer new insights into therapeutic strategies for AD.
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Affiliation(s)
- Abhishek Khatri
- Department of Psychiatry, Institute of Human Behaviour and Allied Sciences (IHBAS), New Delhi, India
| | - Om Prakash
- Department of Psychiatry, Institute of Human Behaviour and Allied Sciences (IHBAS), New Delhi, India
| | - Rachna Agarwal
- Department of Neurochemistry, Institute of Human Behaviour and Allied Sciences (IHBAS), New Delhi, India
| | - Suman Kushwaha
- Department of Neurology, Institute of Human Behaviour and Allied Sciences (IHBAS), New Delhi, India
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da Silva SP, de Castro CCM, Rabelo LN, Engelberth RC, Fernández-Calvo B, Fiuza FP. Neuropathological and sociodemographic factors associated with the cortical amyloid load in aging and Alzheimer's disease. GeroScience 2024; 46:621-643. [PMID: 37870702 PMCID: PMC10828279 DOI: 10.1007/s11357-023-00982-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 10/10/2023] [Indexed: 10/24/2023] Open
Abstract
Alzheimer's disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive abilities. A pathological hallmark of AD is a region-specific accumulation of the amyloid-beta protein (Aβ). Here, we explored the association between regional Aβ deposition, sociodemographic, and local biochemical factors. We quantified the Aβ burden in postmortem cortical samples from parietal (PCx) and temporal (TCx) regions of 27 cognitively unimpaired (CU) and 15 AD donors, aged 78-100 + years. Histological images of Aβ immunohistochemistry and local concentrations of pathological and inflammatory proteins were obtained at the "Aging, Dementia and TBI Study" open database. We used the area fraction fractionator stereological methodology to quantify the Aβ burden in the gray and white matter within each cortical region. We found higher Aβ burdens in the TCx of AD octogenarians compared to CU ones. We also found higher Aβ loads in the PCx of AD nonagenarians than in AD octogenarians. Moreover, AD women exhibited increased Aβ deposition compared to CU women. Interestingly, we observed a negative correlation between education years and Aβ burden in the white matter of both cortices in CU samples. In AD brains, the Aβ40, Aβ42, and pTau181 isoforms of Aβ and Tau proteins were positively correlated with the Aβ burden. Additionally, in the TCx of AD donors, the proinflammatory cytokine TNFα showed a positive correlation with the Aβ load. These novel findings contribute to understanding the interplay between sociodemographic characteristics, local inflammatory signaling, and the development of AD-related pathology in the cerebral cortex.
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Affiliation(s)
- Sayonara P da Silva
- Graduate Program in Neuroengineering, Edmond and Lily Safra International Institute of Neuroscience, Santos Dumont Institute, Macaíba, RN, 59280-000, Brazil
| | - Carla C M de Castro
- Graduate Program in Neuroengineering, Edmond and Lily Safra International Institute of Neuroscience, Santos Dumont Institute, Macaíba, RN, 59280-000, Brazil
| | - Lívia N Rabelo
- Graduate Program in Neuroengineering, Edmond and Lily Safra International Institute of Neuroscience, Santos Dumont Institute, Macaíba, RN, 59280-000, Brazil
- Laboratory of Neurochemical Studies, Department of Physiology and Behavior, Biosciences Center, Federal University of Rio Grande Do Norte, Natal, Brazil
| | - Rovena C Engelberth
- Laboratory of Neurochemical Studies, Department of Physiology and Behavior, Biosciences Center, Federal University of Rio Grande Do Norte, Natal, Brazil
| | - Bernardino Fernández-Calvo
- Department of Psychology, University of Córdoba, Córdoba, Spain
- Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
- Department of Psychology, Federal University of Paraíba, João Pessoa, Brazil
| | - Felipe P Fiuza
- Graduate Program in Neuroengineering, Edmond and Lily Safra International Institute of Neuroscience, Santos Dumont Institute, Macaíba, RN, 59280-000, Brazil.
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11
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Li Z, Wang H, Yin Y. Peripheral inflammation is a potential etiological factor in Alzheimer's disease. Rev Neurosci 2024; 35:99-120. [PMID: 37602685 DOI: 10.1515/revneuro-2023-0049] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/27/2023] [Indexed: 08/22/2023]
Abstract
Peripheral inflammation could constitute a risk factor for AD. This review summarizes the research related to peripheral inflammation that appears to have a relationship with Alzheimer's disease. We find there are significant associations between AD and peripheral infection induced by various pathogens, including herpes simplex virus type 1, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, severe acute respiratory syndrome coronavirus 2, Porphyromonas gingivalis, Helicobacter pylori, and Toxoplasma gondii. Chronic inflammatory diseases are also reported to contribute to the pathophysiology of AD. The mechanisms by which peripheral inflammation affects the pathophysiology of AD are complex. Pathogen-derived neurotoxic molecule composition, disrupted BBB, and dysfunctional neurogenesis may all play a role in peripheral inflammation, promoting the development of AD. Anti-pathogenic medications and anti-inflammatory treatments are reported to decrease the risk of AD. Studies that could improve understanding the associations between AD and peripheral inflammation are needed. If our assumption is correct, early intervention against inflammation may be a potential method of preventing and treating AD.
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Affiliation(s)
- Ziyuan Li
- Department of Nuclear Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Yangpu District, Shanghai 200092, China
| | - Hui Wang
- Department of Nuclear Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Yangpu District, Shanghai 200092, China
| | - Yafu Yin
- Department of Nuclear Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665, Yangpu District, Shanghai 200092, China
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12
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Loeffler DA. Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems. J Alzheimers Dis 2024; 100:379-411. [PMID: 38875041 PMCID: PMC11307100 DOI: 10.3233/jad-240212] [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: 05/14/2024] [Indexed: 06/16/2024]
Abstract
Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer's disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across the capillary endothelia, dissolving Aβ aggregates, and a "peripheral sink" mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone.
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Affiliation(s)
- David A. Loeffler
- Department of Neurology, Beaumont Research Institute, Corewell Health, Royal Oak, MI, USA
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13
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Hui BSM, Zhi LR, Retinasamy T, Arulsamy A, Law CSW, Shaikh MF, Yeong KY. The Role of Interferon-α in Neurodegenerative Diseases: A Systematic Review. J Alzheimers Dis 2023; 94:S45-S66. [PMID: 36776068 PMCID: PMC10473139 DOI: 10.3233/jad-221081] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/30/2022] [Indexed: 02/10/2023]
Abstract
BACKGROUND Neurodegenerative diseases (NDs) impose significant financial and healthcare burden on populations all over the world. The prevalence and incidence of NDs have been observed to increase dramatically with age. Hence, the number of reported cases is projected to increase in the future, as life spans continues to rise. Despite this, there is limited effective treatment against most NDs. Interferons (IFNs), a family of cytokines, have been suggested as a promising therapeutic target for NDs, particularly IFN-α, which governs various pathological pathways in different NDs. OBJECTIVE This systematic review aimed to critically appraise the currently available literature on the pathological role of IFN-α in neurodegeneration/NDs. METHODS Three databases, Scopus, PubMed, and Ovid Medline, were utilized for the literature search. RESULTS A total of 77 journal articles were selected for critical evaluation, based on the inclusion and exclusion criteria. The studies selected and elucidated in this current systematic review have showed that IFN-α may play a deleterious role in neurodegenerative diseases through its strong association with the inflammatory processes resulting in mainly neurocognitive impairments. IFN-α may be displaying its neurotoxic function via various mechanisms such as abnormal calcium mineralization, activation of STAT1-dependent mechanisms, and increased quinolinic acid production. CONCLUSION The exact role IFN-α in these neurodegenerative diseases have yet to be determine due to a lack in more recent evidence, thereby creating a variability in the role of IFN-α. Future investigations should thus be conducted, so that the role played by IFN-α in neurodegenerative diseases could be delineated.
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Affiliation(s)
- Brendan Su Mee Hui
- Clinical School Johor Bahru, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Johor Baru, Johor, Malaysia
| | - Lee Rui Zhi
- Clinical School Johor Bahru, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Johor Baru, Johor, Malaysia
| | - Thaarvena Retinasamy
- Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
| | - Alina Arulsamy
- Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
| | | | - Mohd. Farooq Shaikh
- Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
- School of Dentistry and Medical Sciences, Charles Sturt University, Orange, NSW, Australia
- Department of Neuroscience, Central Clinical School, Monash University, The Alfred Hospital, Melbourne, VIC, Australia
| | - Keng Yoon Yeong
- School of Science, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
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14
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Li RY, Qin Q, Yang HC, Wang YY, Mi YX, Yin YS, Wang M, Yu CJ, Tang Y. TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target. Mol Neurodegener 2022; 17:40. [PMID: 35658903 PMCID: PMC9166437 DOI: 10.1186/s13024-022-00542-y] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 05/09/2022] [Indexed: 12/13/2022] Open
Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane immune receptor that is mainly expressed on microglia in the brain and macrophages in the periphery. Recent studies have identified TREM2 as a risk factor for Alzheimer’s disease (AD). Increasing evidence has shown that TREM2 can affect lipid metabolism both in the central nervous system (CNS) and in the periphery. In the CNS, TREM2 affects the metabolism of cholesterol, myelin, and phospholipids and promotes the transition of microglia into a disease-associated phenotype. In the periphery, TREM2 influences lipid metabolism by regulating the onset and progression of obesity and its complications, such as hypercholesterolemia, atherosclerosis, and nonalcoholic fatty liver disease. All these altered lipid metabolism processes could influence the pathogenesis of AD through several means, including affecting inflammation, insulin resistance, and AD pathologies. Herein, we will discuss a potential pathway that TREM2 mediates lipid metabolism to influence the pathogenesis of AD in both the CNS and periphery. Moreover, we discuss the possibility that TREM2 may be a key factor that links central and peripheral lipid metabolism under disease conditions, including AD. This link may be due to impacts on the integrity of the blood–brain barrier, and we introduce potential pathways by which TREM2 affects the blood–brain barrier. Moreover, we discuss the role of lipids in TREM2-associated treatments for AD. We propose some potential therapies targeting TREM2 and discuss the prospect and limitations of these therapies.
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Affiliation(s)
- Rui-Yang Li
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Qi Qin
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Han-Chen Yang
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Ying-Ying Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Ying-Xin Mi
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Yun-Si Yin
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Meng Wang
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Chao-Ji Yu
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Yi Tang
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China.
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Hao J, Guo Y, Guo K, Yang Q. Peripheral Inflammatory Biomarkers of Alzheimer’s Disease. J Alzheimers Dis 2022; 88:389-398. [PMID: 35599478 DOI: 10.3233/jad-215422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease of unknown pathological origin. The clinical diagnosis of AD is time-consuming and needs to a combination of clinical evaluation, psychological testing, and imaging assessments. Biomarkers may be good indicators for the clinical diagnosis of AD; hence, it is important to identify suitable biomarkers for the diagnosis and treatment of AD. Peripheral inflammatory biomarkers have been the focus of research in recent years. This review summarizes the role of inflammatory biomarkers in the disease course of AD.
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Affiliation(s)
- Jing Hao
- Department of Neurology, Anyang People’s Hospital, Xinxiang Medical University, Anyang, P.R. China
| | - Yanping Guo
- Department of Neurology, Anyang People’s Hospital, Xinxiang Medical University, Anyang, P.R. China
| | - Keke Guo
- Department of Neurology, Anyang People’s Hospital, Xinxiang Medical University, Anyang, P.R. China
| | - Qingcheng Yang
- Department of Neurology, Anyang People’s Hospital, Xinxiang Medical University, Anyang, P.R. China
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Romero-Sevilla R, López-Espuela F, Fuentes JM, de San Juan BD, Portilla-Cuenca JC, Hijon CC, Casado-Naranjo I. Role of Inflammatory Cytokines in the Conversion of Mild Cognitive Im- pairment to Dementia: A Prospective Study. Curr Alzheimer Res 2022; 19:68-75. [PMID: 35086447 DOI: 10.2174/1567205019666220127102640] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 09/13/2021] [Accepted: 10/08/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The effect that cytokines can exert on the progression from mild cognitive impairment (MCI) to ongoing dementia is a matter of debate and the results obtained so far are controversial. OBJECTIVE The aim of the study is to analyze the influence of markers of subclinical inflammation on the progression of MCI to dementia. METHODS A prospective study involving a cohort of patients ≥ 65 years of age diagnosed with MCI and followed for 3 years was conducted. 105 patients were enrolled, and serum concentrations of several subclinical inflammatory markers were determined. RESULTS After 3.09 (2 - 3.79) years of follow-up, 47 (44.76%) patients progressed to dementia. Alpha 1-antichymotrypsin (ACT) was found to be significantly higher in patients who progressed to dementia (486.45 ± 169.18 vs. 400.91 ± 163.03; p = 0.012), and observed to significantly increase the risk of developing dementia in patients with mild cognitive impairment (1.004, 1.001-1.007; p= 0.007). IL-10 levels were significantly higher in those who remained stable (6.69 ± 18.1 vs. 32.54 ± 89.6; p = 0.04). Regarding the type of dementia to which our patients progressed, we found that patients who developed mixed dementia had higher IL-4 levels than those who converted to AD (31.54 ± 63.6 vs. 4.43 ± 12.9; p = 0.03). No significant differences were observed between the groups with regard to the ESR and LPa, CRP, IL-1 and TNF-α levels. CONCLUSION ACT levels have a significant predictive value in the conversion of MCI to dementia. IL-10 levels could be a protective factor. It is necessary to conduct studies with serial determinations of these and other inflammatory markers in order to determine their effect on the progression of MCI to dementia.
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Affiliation(s)
| | - Fidel López-Espuela
- Nursing Department. Nursing and Occupational Therapy College, University of Extremadura. Cáceres, Spain
| | - José Manuel Fuentes
- Department of Biochemistry and Molecular Biology and Genetics. Nursing and Occupational Therapy College, University of Extremadura, Cáceres, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED) Madrid, Spain
- Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE), Caceres, Spain
| | | | | | | | - Ignacio Casado-Naranjo
- Department of Neurology, Hospital Universitario de Caceres, Cáceres, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED) Madrid, Spain
- Instituto Universitario de Investigación Biosanitaria de Extremadura (INUBE), Caceres, Spain
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Zheng Y, Ji B, Chen S, Zhou R, Ni R. The impact of uremic toxins on Alzheimer's disease. Curr Alzheimer Res 2022; 19:104-118. [PMID: 35048807 DOI: 10.2174/1567205019666220120113305] [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: 08/18/2021] [Revised: 11/27/2021] [Accepted: 12/14/2021] [Indexed: 11/22/2022]
Abstract
Alzheimer's disease (AD) is the most common type of dementia, pathologically characterized by accumulation of senile plaques and neurofibrillary tangles. Chronic kidney disease (CKD) is highly prevalent in elderly population closely associated with occurrence of dementia. Recent epidemiological and experimental studies suggest a potential association of CKD with AD. Both diseases share a panel of identical risk factors, such as type 2 diabetes; and hypertension. However, the relationship between CKD and AD is unclear. Lower clearance of a panel of uremic toxin including cystatin-C, guanidine, and adiponectin due to CKD is implied to contribute to AD pathogenesis. In this review we summarize the current evidence from epidemiological, experimental and clinical studies on the potential contribution of uremic toxins to AD pathogenesis. We describe outstanding questions and propose an outlook on the link between uremic toxins and AD.
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Affiliation(s)
- Yuqi Zheng
- Department of Nephrology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bin Ji
- Department of Radiopharmacy and Molecular Imaging, School of Pharmacy, Fudan University, Shanghai, China
| | - Sijun Chen
- Department of Nephrology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Rong Zhou
- Department of Nephrology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ruiqing Ni
- Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland
- Institute for Biomedical Engineering, University of Zurich & ETH Zurich, Zurich, Switzerland
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18
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da Rosa MM, de Aguiar Ferreira M, de Oliveira Lima CA, Santos Mendonça AC, Silva YM, Sharjeel M, de Melo Rego MJB, Pereira MC, da Rocha Pitta MG. Alzheimer's disease: Is there a role for galectins? Eur J Pharmacol 2021; 909:174437. [PMID: 34450113 DOI: 10.1016/j.ejphar.2021.174437] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/16/2021] [Accepted: 08/17/2021] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is the world's leading cause of neurological dysfunction, cognitive decline, and neuronal loss in the elderly. The sedimentation of beta amyloid (Aβ)-containing plaque, and formation of tau-containing neurofibrillary tangles (NFTs) along with extensive neuroinflammation, are the events that characterize the pathogenesis of AD. Galectins (gal) are carbohydrate-containing-ligand molecules recognized as potential modulators of the brain microglia polarization, immunosurveillance, neuroinflammation, and neuroprotection. Galectins 1, 3, 4, 8, and 9 are amongst the 15 members of the galectin family which are expressed in the brain. These galectins possess a significant correlation with neuromodulation through the glial cell-induced cytokine production that plays either a complementary or antagonistic role in the disturbance of the CNS physiology. Therefore, elaborating the hypothesis of galectins in the development of AD is of potential interest. This review aims at discussing the interaction between galectins and the neuropathophysiology of AD. An understanding about how galectins communicate with AD progression could lead to the development of improved diagnostic and therapeutic strategies for this leading cause of dementia worldwide.
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Affiliation(s)
- Michelle Melgarejo da Rosa
- Department of Biochemistry, Federal University of Pernambuco, Recife, Brazil; Center for Therapeutic Innovation - Suelly Galdino (NUPIT-SG), Recife, Brazil.
| | | | | | | | | | | | | | - Michelly Cristiny Pereira
- Center for Therapeutic Innovation - Suelly Galdino (NUPIT-SG), Recife, Brazil; Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, Brazil
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Blood-Based Biomarkers of Neuroinflammation in Alzheimer's Disease: A Central Role for Periphery? Diagnostics (Basel) 2021; 11:diagnostics11091525. [PMID: 34573867 PMCID: PMC8464786 DOI: 10.3390/diagnostics11091525] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/17/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022] Open
Abstract
Neuroinflammation represents a central feature in the development of Alzheimer’s disease (AD). The resident innate immune cells of the brain are the principal players in neuroinflammation, and their activation leads to a defensive response aimed at promoting β-amyloid (Aβ) clearance. However, it is now widely accepted that the peripheral immune system—by virtue of a dysfunctional blood–brain barrier (BBB)—is involved in the pathogenesis and progression of AD; microglial and astrocytic activation leads to the release of chemokines able to recruit peripheral immune cells into the central nervous system (CNS); at the same time, cytokines released by peripheral cells are able to cross the BBB and act upon glial cells, modifying their phenotype. To successfully fight this neurodegenerative disorder, accurate and sensitive biomarkers are required to be used for implementing an early diagnosis, monitoring the disease progression and treatment effectiveness. Interestingly, as a result of the bidirectional communication between the brain and the periphery, the blood compartment ends up reflecting several pathological changes occurring in the AD brain and can represent an accessible source for such biomarkers. In this review, we provide an overview on some of the most promising peripheral biomarkers of neuroinflammation, discussing their pathogenic role in AD.
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Diabetes and Alzheimer's Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path? Antioxidants (Basel) 2021; 10:antiox10081257. [PMID: 34439505 PMCID: PMC8389322 DOI: 10.3390/antiox10081257] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023] Open
Abstract
A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer's disease (AD). Indeed, the proposed definition of Alzheimer's disease as type 3 diabetes (T3D) underlines the key role played by deranged insulin signaling to accumulation of aggregated amyloid beta (Aβ) peptides in the senile plaques of the brain. Metabolic disturbances such as hyperglycemia, peripheral hyperinsulinemia, dysregulated lipid metabolism, and chronic inflammation associated with T2DM are responsible for an inefficient transport of insulin to the brain, producing a neuronal insulin resistance that triggers an enhanced production and deposition of Aβ and concomitantly contributes to impairment in the micro-tubule-associated protein Tau, leading to neural degeneration and cognitive decline. Furthermore, the reduced antioxidant capacity observed in T2DM patients, together with the impairment of cerebral glucose metabolism and the decreased performance of mitochondrial activity, suggests the existence of a relationship between oxidative damage, mitochondrial impairment, and cognitive dysfunction that could further reinforce the common pathophysiology of T2DM and AD. In this review, we discuss the molecular mechanisms by which insulin-signaling dysregulation in T2DM can contribute to the pathogenesis and progression of AD, deepening the analysis of complex mechanisms involved in reactive oxygen species (ROS) production under oxidative stress and their possible influence in AD and T2DM. In addition, the role of current therapies as tools for prevention or treatment of damage induced by oxidative stress in T2DM and AD will be debated.
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van Soest APM, van de Rest O, Witkamp RF, de Groot LCPGM. Positive effects of folic acid supplementation on cognitive aging are dependent on ω-3 fatty acid status: a post hoc analysis of the FACIT trial. Am J Clin Nutr 2021; 113:801-809. [PMID: 33564824 DOI: 10.1093/ajcn/nqaa373] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/16/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Although epidemiological studies suggest a protective role of B vitamins and omega-3 (ω-3) fatty acids in cognitive decline, findings from intervention studies are conflicting. Mechanistic studies suggest that the ω-3 (n-3) fatty acid status can modulate the effects of B vitamins on cognitive decline. OBJECTIVES We investigated the interaction between baseline ω-3 fatty acid statuses and folic acid treatment on cognitive decline in a placebo-controlled trial [FACIT (Folic Acid and Carotid Intima-media Thickness)]. METHODS This post hoc analysis included 791 older adults aged 50-70 y with plasma total homocysteine ≥13 µmol/L and ≤26 µmol/L and serum vitamin B12 ≥200 pmol/L. Participants received 800 µg folic acid or placebo daily for 3 y. Global cognitive functioning and domain-specific functioning (episodic memory, information processing speed, executive functioning) were assessed at baseline and after 3 y. The effect of the folic acid supplementation was analyzed according to tertiles of baseline ω-3 fatty acid concentrations using linear multiple regression. RESULTS The mean ± SD age of the study population was 60.2 ± 5.6 y, and the mean ± SD Mini-Mental State Examination score was 28.6 ± 1.5. The treatment effect of folic acid was significantly larger in participants in the low compared to high ω-3 fatty acid tertile for global cognition (difference in z-score: mean ± SE = 0.16 ± 0.059; P < 0.01). Regarding domain-specific functioning, similar results were observed for information processing speed (mean ± SE = 0.167 ± 0.068; P = 0.01). There were no overall interactions between folic acid treatment and ω-3 fatty acid tertiles for episodic memory (P = 0.14) and executive functioning (P = 0.21). CONCLUSIONS This post hoc analysis revealed that the efficacy of folic acid treatment on cognitive functioning is dependent on the ω-3 fatty acid status. Individuals with a lower ω-3 fatty acid status at baseline benefited from folic acid treatment, while individuals with a higher ω-3 fatty acid status did not. The results potentially explain the inconsistency in outcomes of B-vitamin supplementation trials and emphasize the importance of a personalized approach. This trial was registered at clinicaltrials.gov as NCT00110604.
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Affiliation(s)
- Annick P M van Soest
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands
| | - Ondine van de Rest
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands
| | - Renger F Witkamp
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands
| | - Lisette C P G M de Groot
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands
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22
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Odaka H, Hiemori K, Shimoda A, Akiyoshi K, Tateno H. Platelet-derived extracellular vesicles are increased in sera of Alzheimer's disease patients, as revealed by Tim4-based assays. FEBS Open Bio 2021; 11:741-752. [PMID: 33345458 PMCID: PMC7931225 DOI: 10.1002/2211-5463.13068] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/18/2020] [Accepted: 12/18/2020] [Indexed: 12/28/2022] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia, characterized by the accumulation of β‐amyloid plaques and the formation of neurofibrillary tangles. Extracellular vesicles (EVs) are small vesicles surrounded by a lipid bilayer membrane, which may be involved in the progression of AD. Glycans are essential building blocks of EVs, and we hypothesized that EV glycans may reflect pathological conditions of various diseases. Here, we performed glycan profiling of EVs prepared from sera of three AD patients (APs) compared to three healthy donors (HDs) using lectin microarray. Distinct glycan profiles were observed. Mannose‐binding lectins exhibited significantly higher signals for AP‐derived EVs than HD‐derived EVs. Lectin blotting using mannose‐binding lectin (rPALa) showed a single protein band at ~ 80 kDa exclusively in AP‐derived EVs. LC‐MS/MS analysis identified a protein band precipitated by rPALa as CD61, a marker of platelet‐derived exosomes (P‐Exo). Sandwich assays using Tim4 with specificity for phosphatidylserine on EVs and antibodies against P‐Exo markers (CD61, CD41, CD63, and CD9) revealed that P‐Exo is significantly elevated in sera of APs (n = 16) relative to age‐ and sex‐matched HDs (n = 16). Tim4‐αCD63 showed the highest value for the area under the curve (0.957) for discriminating APs from HDs, which should lead to a better understanding of AD pathology and may facilitate the development of a novel diagnostic method for AD.
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Affiliation(s)
- Haruki Odaka
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
| | - Keiko Hiemori
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
| | - Asako Shimoda
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Japan
| | - Kazunari Akiyoshi
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Japan
| | - Hiroaki Tateno
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
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23
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Rymaszewska J, Lion KM, Stańczykiewicz B, Rymaszewska JE, Trypka E, Pawlik-Sobecka L, Kokot I, Płaczkowska S, Zabłocka A, Szcześniak D. The improvement of cognitive deficits after whole-body cryotherapy - A randomised controlled trial. Exp Gerontol 2021; 146:111237. [PMID: 33454354 DOI: 10.1016/j.exger.2021.111237] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 11/20/2020] [Accepted: 01/04/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Whole-body cryotherapy (WBC) - a repetitive, short-term exposure to extremely low temperatures - may become an effective early intervention for mild cognitive impairment (MCI). It is a heterogeneous group of symptoms associated with cognitive dysfunction which is estimated to transform into dementia in 50% cases. STUDY DESIGN The prospective randomised double-blind sham-controlled study aimed to determine the efficacy of WBC on cognitive functioning and biological mechanisms. The study was registered with Australian New Zealand Clinical Trials Registry (ACTRN12619001627145). METHODS Participants with MCI (n = 62; (20<MoCA>26) were randomly allocated to cryogenic temperatures (-110 °C till -160 °C) (EG, n = 33) or placebo-controlled group (CG, n = 29). Cognitive functions were measured at baseline (T1), after the 10th WBC session (T2) and after 2 week-break (T3) with DemTect, SLUMS and Test Your Memory (TYM). Secondary outcome measures included quality of life (WHOQoL-BREF), self-reported well-being (VAS) and depressive symptoms (GDS). Whole blood samples (10 ml) were collected at T1 and T2 to evaluate levels of cytokines, neurotrophins, NO and biochemical parameters CRP total cholesterol, prolactin). RESULTS There were significant differences between groups measured at T2 in immediate recall (DemTect) and in orientation (TYM) in favour of WBC group. Improvement in mood was detected in self-reported depressive symptoms level (WHOQoL-26; T2 p = 0.04; VAS mood T2 p = 0.02; T3 p = 0.07). The significant reduction of BDNF level was observed (p < 0.05). CONCLUSIONS WBC may increase the performance of cognitive functions. It seems promising to combine WBC with existing behavioural and cognitive trainings in the future studies investigating early interventions methods in MCI.
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Affiliation(s)
| | - Katarzyna M Lion
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland; Menzies Health Institute Queensland, Griffith University, Australia.
| | | | - Julia E Rymaszewska
- Student Scientific Association at Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
| | - Elżbieta Trypka
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
| | - Lilla Pawlik-Sobecka
- Department of Nervous System Diseases, Wroclaw Medical University, Wroclaw, Poland
| | - Izabela Kokot
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | - Sylwia Płaczkowska
- Department of Laboratory Diagnostics, Diagnostics Laboratory for Teaching and Research, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | - Agnieszka Zabłocka
- Laboratory of Microbiome Immunobiology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Dorota Szcześniak
- Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland
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24
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Wang X, Miao Z, Xu X, Schultzberg M, Zhao Y. Reduced Levels of Plasma Lipoxin A4 Are Associated with Post-Stroke Cognitive Impairment. J Alzheimers Dis 2020; 79:607-613. [PMID: 33337374 DOI: 10.3233/jad-201050] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Specialized pro-resolving mediators (SPMs) are bioactive lipids derived from n-3 and n-6 polyunsaturated fatty acids. SPMs promote resolution of inflammation and are reduced in Alzheimer's disease. It is unknown whether SPMs are associated with post-stroke cognitive impairment (PSCI). OBJECTIVE In the present report, we aimed to study the levels of SPMs in PSCI patients in the acute phase of ischemic stroke. METHODS Levels of SPMs in the plasma from 36 patients with PSCI and 33 patients with post-stroke non-cognitive impairment (PSNCI) were measured by enzyme immunoassay. RESULTS We found that levels of the SPM lipoxin A4 (LXA4) were significantly reduced in PSCI patients compared with PSNCI patients. Interestingly, the LXA4 levels were positively correlated with Mini-Mental State Examination scores, but not with the National Institutes of Health Stroke Scale scores. Such alteration and correlation were not found in any of the other SPMs analyzed, i.e., including resolvin D1, resolvin D2, and maresin 1. CONCLUSION We conclude that the plasma levels of LXA4 were reduced in PSCI patents in the acute phase of ischemic stroke and were correlated to cognitive function.
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Affiliation(s)
- Xiuzhe Wang
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhijuan Miao
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaofeng Xu
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Marianne Schultzberg
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Yuwu Zhao
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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25
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Zhu N, Liang X, Zhang M, Yin X, Yang H, Zhi Y, Ying G, Zou J, Chen L, Yao X, Li H. Astaxanthin protects cognitive function of vascular dementia. BEHAVIORAL AND BRAIN FUNCTIONS : BBF 2020; 16:10. [PMID: 33208152 PMCID: PMC7672991 DOI: 10.1186/s12993-020-00172-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 11/02/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The purpose of this study was to evaluate the effect of astaxanthin (AST) on cognition function, inflammatory response and oxidative stress in vascular dementia (VD) mice. METHOD VD mice model was established by left unilateral common carotid arteries occlusion (LUCCAO). Following LUCCAO, AST was intragastrically administered for 30 days. Object recognition test and morris water maze test were used to evaluate cognitive function. Hematoxylin and eosin staining was performed to observe the hippocampal neuron structure. Enzyme-linked immunosorbent assay kit and bicinchoninic acid kit were respectively adopted to measure IL-1β and IL-4 protein expression and superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in hippocampus and prefrontal cortex. RESULTS AST improved the discrimination ability of VD mice. The escape latency and path length of VD mice treated with AST were dramatically reduced. Besides, AST 200 mg/kg enhanced crossing platform time and the number of times crossing the platform quadrant, and alleviated the morphological impairment in VD mice. Moreover, we found that AST inhibited IL-1β expression and MDA content, whereas promoted IL-4 expression and SOD activity in a dose-dependent manner. CONCLUSION AST could improve cognitive impairment and hippocampal neurons in VD mice, which may be related to suppression of inflammatory response and oxidative stress.
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Affiliation(s)
- Ningwei Zhu
- Department of Pharmacy, Zhejiang Pharmaceutical College, 888 Yinxian Road, YinZhou District, Ningbo, 315000, Zhejiang, China
| | - Xiao Liang
- Department of Neurology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Ming Zhang
- Department of Pharmacy, Ningbo Yinzhou No. 2 Hospital, Ningbo, 315000, Zhejiang, China
| | - Xiaolan Yin
- Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Hui Yang
- Department of Pharmacy, Zhejiang Pharmaceutical College, 888 Yinxian Road, YinZhou District, Ningbo, 315000, Zhejiang, China
| | - Yajun Zhi
- Department of Pharmacy, Zhejiang Pharmaceutical College, 888 Yinxian Road, YinZhou District, Ningbo, 315000, Zhejiang, China
| | - Guizhen Ying
- Department of Pharmacy, Zhejiang Pharmaceutical College, 888 Yinxian Road, YinZhou District, Ningbo, 315000, Zhejiang, China
| | - Jialing Zou
- Department of Pharmacy, Zhejiang Pharmaceutical College, 888 Yinxian Road, YinZhou District, Ningbo, 315000, Zhejiang, China
| | - Lei Chen
- Department of Pharmacy, Zhejiang Pharmaceutical College, 888 Yinxian Road, YinZhou District, Ningbo, 315000, Zhejiang, China
| | - Xiaokun Yao
- Department of Pharmacy, Zhejiang Pharmaceutical College, 888 Yinxian Road, YinZhou District, Ningbo, 315000, Zhejiang, China
| | - Hongwei Li
- Department of Pharmacy, Zhejiang Pharmaceutical College, 888 Yinxian Road, YinZhou District, Ningbo, 315000, Zhejiang, China.
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26
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Fuller OK, Whitham M, Mathivanan S, Febbraio MA. The Protective Effect of Exercise in Neurodegenerative Diseases: The Potential Role of Extracellular Vesicles. Cells 2020; 9:cells9102182. [PMID: 32998245 PMCID: PMC7599526 DOI: 10.3390/cells9102182] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/18/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023] Open
Abstract
Physical activity has systemic effects on the body, affecting almost every organ. It is important not only for general health and wellbeing, but also in the prevention of diseases. The mechanisms behind the therapeutic effects of physical activity are not completely understood; however, studies indicate these benefits are not confined to simply managing energy balance and body weight. They also include systemic factors which are released into the circulation during exercise and which appear to underlie the myriad of benefits exercise can elicit. It was shown that along with a number of classical cytokines, active tissues also engage in inter-tissue communication via extracellular vesicles (EVs), specifically exosomes and other small EVs, which are able to deliver biomolecules to cells and alter their metabolism. Thus, EVs may play a role in the acute and systemic adaptations that take place during and after physical activity, and may be therapeutically useful in the treatment of a range of diseases, including metabolic disorders such as type 2 diabetes and obesity; and the focus of this review, neurological disorders such as Alzheimer's disease.
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Affiliation(s)
- Oliver K Fuller
- Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia;
| | - Martin Whitham
- College of Life and Environmental Sciences, University of Birmingham, Edgbaston B15 2TT, UK;
| | - Suresh Mathivanan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3083, Australia;
| | - Mark A Febbraio
- Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia;
- Correspondence:
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27
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Current Evidence Regarding Biomarkers Used to Aid Postoperative Delirium Diagnosis in the Field of Cardiac Surgery-Review. ACTA ACUST UNITED AC 2020; 56:medicina56100493. [PMID: 32987655 PMCID: PMC7598630 DOI: 10.3390/medicina56100493] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/17/2020] [Accepted: 09/22/2020] [Indexed: 12/16/2022]
Abstract
Postoperative cognitive disorders after cardiac surgery may manifest as postoperative delirium (POD) or later as postoperative cognitive dysfunction (POCD). The incidence of POD after cardiac surgery ranges from 16% to 73%. In contrast to POD, POCD is usually diagnosed after the discharge from hospital, with an incidence of 30 to 70% of cases, very often noticed only by close relative or friends, decreasing after six (20–30%) and twelve (15–25%) months after surgery. Perioperative cognitive disorders are associated with adverse short- and long-term effects, including increased morbidity and mortality. Due to the complexity of delirium pathomechanisms and the difficulties in the diagnosis, researchers have not yet found a clear answer to the question of which patient will be at a higher risk of developing delirium. The risk for POD and POCD in older patients with numerous comorbidities like hypertension, diabetes, and previous ischemic stroke is relatively high, and the predisposing cognitive profile for both conditions is important. The aim of this narrative review was to identify and describe biomarkers used in the diagnosis of delirium after cardiac surgery by presenting a search through studies regarding this subject, which have been published during the last ten years. The authors discussed brain-derived biomarkers, inflammation-related biomarkers, neurotransmitter-based biomarkers, and others. Work based on inflammation-related biomarkers, which are characterized by the low cost of implementation and the effectiveness of delirium diagnosis, seems to be the closest to the goal of discovering an inexpensive and effective marker. Currently, the use of a panel of tests, and not a single biomarker, brings us closer to the discovery of a test, or rather a set of tests ideal for the diagnosis of delirium after cardiac surgery.
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28
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Whiten DR, Brownjohn PW, Moore S, De S, Strano A, Zuo Y, Haneklaus M, Klenerman D, Livesey FJ. Tumour necrosis factor induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer's disease neurons. Brain Commun 2020; 2:fcaa146. [PMID: 33543132 PMCID: PMC7850285 DOI: 10.1093/braincomms/fcaa146] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 07/21/2020] [Accepted: 07/27/2020] [Indexed: 01/24/2023] Open
Abstract
In addition to increased aberrant protein aggregation, inflammation has been proposed as a key element in the pathogenesis and progression of Alzheimer’s disease. How inflammation interacts with other disease pathways and how protein aggregation increases during disease are not clear. We used single-molecule imaging approaches and membrane permeabilization assays to determine the effect of chronic exposure to tumour necrosis factor, a master proinflammatory cytokine, on protein aggregation in human-induced pluripotent stem cell-derived neurons harbouring monogenic Alzheimer’s disease mutations. We report that exposure of Alzheimer’s disease neurons, but not control neurons, to tumour necrosis factor induces substantial production of extracellular protein aggregates. Aggregates from Alzheimer’s disease neurons are composed of amyloid-β and α-synuclein and induce significant permeabilization of lipid membranes in an assay of pathogenicity. These findings provide support for a causal relationship between two crucial processes in Alzheimer’s disease pathogenesis and suggest that targeting inflammation, particularly tumour necrosis factor, may have beneficial downstream effects on ameliorating aberrant protein aggregation and accumulation.
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Affiliation(s)
- Daniel R Whiten
- Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
| | - Philip W Brownjohn
- Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, UK
| | - Steven Moore
- Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, UK
| | - Suman De
- Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
| | - Alessio Strano
- Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, UK
| | - Yukun Zuo
- Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
| | - Moritz Haneklaus
- Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, UK
| | - David Klenerman
- Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.,UK Dementia Research Institute at University of Cambridge, Cambridge CB2 0XY, UK
| | - Frederick J Livesey
- Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London WC1N 1DZ, UK
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29
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Ruthirakuhan M, Herrmann N, Andreazza AC, Verhoeff NPLG, Gallagher D, Black SE, Kiss A, Lanctôt KL. Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation. J Geriatr Psychiatry Neurol 2020; 33:175-184. [PMID: 31547752 DOI: 10.1177/0891988719874118] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; F1, 35 = 6.41, P = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; F1, 29 = 3.97, P = .06), were associated with agitation severity, and TNF-α remained significantly associated (F2, 25 = 3.69, P = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, P = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, P = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, P = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, P = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.
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Affiliation(s)
- Myuri Ruthirakuhan
- Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Nathan Herrmann
- Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.,Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Ana C Andreazza
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Nicolaas Paul L G Verhoeff
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.,Department of Psychiatry, Baycrest Health Science Centre, Toronto, Ontario, Canada
| | - Damien Gallagher
- Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.,Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Sandra E Black
- Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Alex Kiss
- Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Krista L Lanctôt
- Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.,Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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30
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Sedighi M, Baluchnejadmojarad T, Fallah S, Moradi N, Afshin-Majd S, Roghani M. The Association Between Circulating Klotho and Dipeptidyl Peptidase-4 Activity and Inflammatory Cytokines in Elderly Patients With Alzheimer Disease. Basic Clin Neurosci 2020; 11:349-357. [PMID: 32963727 PMCID: PMC7502192 DOI: 10.32598/bcn.11.2.1747.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/05/2019] [Accepted: 10/15/2019] [Indexed: 12/16/2022] Open
Abstract
Introduction: Klotho and Dipeptidyl Peptidase-4 (DPP4) are two proteins that modulate inflammatory pathways. We investigated the association between circulating klotho and DPP4 activity and their relationship with inflammatory cytokines, miR-29a, and miR-195 in Alzheimer Disease (AD). Methods: This study was conducted on 16 AD patients and 16 healthy age-matched controls. Plasma levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β, interleukin-6 (IL-6), klotho, and DPP4 were measured by enzyme-linked immunosorbent assay. Plasma expression of miR-29a and miR-195 were also measured and compared by a real-time polymerase chain reaction. Results: There was a significant increase in TNF-α (p=0.006), IL-1β (p=0.012), and IL-6 (p=0.012) levels in the AD subjects compared with controls. Also, we found a decrease in plasma levels of klotho and an increase in plasma levels of DPP4 in the AD group that was not significant compared with the controls. Lower expression of miR-29a (P=0.009) and higher expression of miR-195 (P=0.003) were observed in the AD group that was significant than controls. Further analysis showed a negative correlation between klotho and plasma levels of IL-6 (r=−0.58, p=0.01). Also, there was a positive correlation between plasma DPP4 activity and TNF-α levels (r=0.50, P=0.04) and IL-1β (r=0.62, P=0.01). Likewise, plasma klotho concentration showed a negative correlation with the age of AD subjects (r=−0.56, P=0.02). Conclusion: TNF-α, IL-1β, and IL-6 are involved in AD pathophysiology, and dysregulation of DPP4 and klotho may be associated with the inflammatory response of AD. Down-regulation of miR-29a and up-regulation of miR-195 indicated the role of miRNAs in the AD process.
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Affiliation(s)
- Mohsen Sedighi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.,Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Tourandokht Baluchnejadmojarad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Soudabeh Fallah
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nariman Moradi
- Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Siamak Afshin-Majd
- Neurophysiology Research Center, Shahed University, Tehran, Iran.,Department of Neurology, School of Medicine, Shahed University, Tehran, Iran
| | - Mehrdad Roghani
- Neurophysiology Research Center, Shahed University, Tehran, Iran
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Picca A, Ronconi D, Coelho-Junior HJ, Calvani R, Marini F, Biancolillo A, Gervasoni J, Primiano A, Pais C, Meloni E, Fusco D, Lo Monaco MR, Bernabei R, Cipriani MC, Marzetti E, Liperoti R. The "develOpment of metabolic and functional markers of Dementia IN Older people" (ODINO) Study: Rationale, Design and Methods. J Pers Med 2020; 10:E22. [PMID: 32283734 PMCID: PMC7354545 DOI: 10.3390/jpm10020022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/03/2020] [Accepted: 04/04/2020] [Indexed: 02/06/2023] Open
Abstract
Mild cognitive impairment (MCI), also termed mild neurocognitive disorder, includes a heterogeneous group of conditions characterized by declines in one or more cognitive domains greater than that expected during "normal" aging but not severe enough to impair functional abilities. MCI has been associated with an increased risk of developing dementia and even considered an early stage of it. Therefore, noninvasively accessible biomarkers of MCI are highly sought after for early identification of the condition. Systemic inflammation, metabolic perturbations, and declining physical performance have been described in people with MCI. However, whether biological and functional parameters differ across MCI neuropsychological subtypes is presently debated. Likewise, the predictive value of existing biomarkers toward MCI conversion into dementia is unclear. The "develOpment of metabolic and functional markers of Dementia IN Older people" (ODINO) study was conceived as a multi-dimensional investigation in which multi-marker discovery will be coupled with innovative statistical approaches to characterize patterns of systemic inflammation, metabolic perturbations, and physical performance in older adults with MCI. The ultimate aim of ODINO is to identify potential biomarkers specific for MCI subtypes and predictive of MCI conversion into Alzheimer's disease or other forms of dementia over a three-year follow-up. Here, we describe the rationale, design, and methods of ODINO.
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Affiliation(s)
- Anna Picca
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
| | - Daniela Ronconi
- Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.R.); (H.J.C.-J.)
| | | | - Riccardo Calvani
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
| | - Federico Marini
- Department of Chemistry, Sapienza Università di Roma, 00185 Rome, Italy;
| | - Alessandra Biancolillo
- Department of Physical and Chemical Sciences, Università degli Studi dell’Aquila, 67100 L’Aquila, Italy;
| | - Jacopo Gervasoni
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
- Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.R.); (H.J.C.-J.)
| | - Aniello Primiano
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
- Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.R.); (H.J.C.-J.)
| | - Cristina Pais
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
| | - Eleonora Meloni
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
| | - Domenico Fusco
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
| | - Maria Rita Lo Monaco
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
| | - Roberto Bernabei
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
- Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.R.); (H.J.C.-J.)
| | - Maria Camilla Cipriani
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
| | - Emanuele Marzetti
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
- Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.R.); (H.J.C.-J.)
| | - Rosa Liperoti
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy; (A.P.); (R.C.); (J.G.); (A.P.); (C.P.); (E.M.); (D.F.); (M.R.L.M.); (M.C.C.); (R.L.)
- Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.R.); (H.J.C.-J.)
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Hampel H, Caraci F, Cuello AC, Caruso G, Nisticò R, Corbo M, Baldacci F, Toschi N, Garaci F, Chiesa PA, Verdooner SR, Akman-Anderson L, Hernández F, Ávila J, Emanuele E, Valenzuela PL, Lucía A, Watling M, Imbimbo BP, Vergallo A, Lista S. A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease. Front Immunol 2020; 11:456. [PMID: 32296418 PMCID: PMC7137904 DOI: 10.3389/fimmu.2020.00456] [Citation(s) in RCA: 216] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 02/27/2020] [Indexed: 12/13/2022] Open
Abstract
Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants—TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1—potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish in vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal–spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker–drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.
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Affiliation(s)
- Harald Hampel
- Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
| | - Filippo Caraci
- Department of Drug Sciences, University of Catania, Catania, Italy.,Oasi Research Institute-IRCCS, Troina, Italy
| | - A Claudio Cuello
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.,Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.,Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | | | - Robert Nisticò
- Laboratory of Neuropharmacology, EBRI Rita Levi-Montalcini Foundation, Rome, Italy.,School of Pharmacy, Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Massimo Corbo
- Department of Neurorehabilitation Sciences, Casa Cura Policlinico, Milan, Italy
| | - Filippo Baldacci
- Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.,Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France.,Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.,Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Nicola Toschi
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.,Department of Radiology, "Athinoula A. Martinos" Center for Biomedical Imaging, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States
| | - Francesco Garaci
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.,Casa di Cura "San Raffaele Cassino", Cassino, Italy
| | - Patrizia A Chiesa
- Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.,Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France.,Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | | | | | - Félix Hernández
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.,Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Jesús Ávila
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.,Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | | | | | - Alejandro Lucía
- Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain.,Research Institute of the Hospital 12 de Octubre ("imas"), Madrid, Spain.,Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain
| | | | - Bruno P Imbimbo
- Research & Development Department, Chiesi Farmaceutici, Parma, Italy
| | - Andrea Vergallo
- Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France
| | - Simone Lista
- Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.,Brain & Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France.,Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
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Wang X, Liu G, Gao Q, Li N, Wang R. C-type lectin-like receptor 2 and zonulin are associated with mild cognitive impairment and Alzheimer's disease. Acta Neurol Scand 2020; 141:250-255. [PMID: 31715011 DOI: 10.1111/ane.13196] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 11/02/2019] [Accepted: 11/09/2019] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Increased permeability and changes in gut microbiota contributed to the pathogenesis of Alzheimer's disease (AD). Zonulin is a key modulator that regulates intestinal barrier function. Peripheral platelet alterations have been involved in AD pathology. C-type lectin-like receptor 2 (CLEC-2) is a receptor on the platelet surface for activation. The purpose of this study was to determine zonulin and CLEC-2 levels in mild cognitive impairment (MCI) and AD, and investigate the relationship between zonulin and CLEC-2. METHODS In this study, CLEC-2 and zonulin levels were measured using ELISA assay in 110 AD patients, 110 MCI patients, and 110 non-demented control subjects. RESULTS Increased CLEC-2 and zonulin levels were observed in MCI and AD patients. Furthermore, AD patients had higher CLEC-2 and zonulin levels compared with MCI patients. In addition, CLEC-2 levels were positively correlated with zonulin levels, after adjusting confounding factors (r = .592, P < .001). Multivariate analysis revealed that increased CLEC-2 and zonulin levels were significantly associated with reduced Mini-Mental State Examination (MMSE) score. CONCLUSIONS C-type lectin-like receptor 2 is correlated with zonulin after adjusting confounding covariates. Moreover, increased CLEC-2 and zonulin are the significant factors for reduced MMSE score in MCI and AD. Further studies are needed.
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Affiliation(s)
- Xin Wang
- Department of Internal Medicine Harbin Medical University Cancer Hospital Harbin Medical University Harbin Heilongjiang China
| | - Guo‐Jun Liu
- Department of Rehabilitation Medicine General Hospital of Heilongjiang General Administration of Agriculture and Reclamation Harbin Heilongjiang China
| | - Qiang Gao
- Department of Geriatrics The Second Affiliated Hospital Harbin Medical University Harbin Heilongjiang China
| | - Na Li
- Department of Internal Medicine Harbin Medical University Cancer Hospital Harbin Medical University Harbin Heilongjiang China
| | - Rui‐tao Wang
- Department of Internal Medicine Harbin Medical University Cancer Hospital Harbin Medical University Harbin Heilongjiang China
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34
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Oxidative Damage of DNA as Early Marker of Alzheimer's Disease. Int J Mol Sci 2019; 20:ijms20246136. [PMID: 31817451 PMCID: PMC6940966 DOI: 10.3390/ijms20246136] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/28/2019] [Accepted: 12/03/2019] [Indexed: 11/16/2022] Open
Abstract
Alzheimer’s Disease (AD) is the most common cause of dementia, and its characteristic histopathological hallmarks are neurofibrillary tangles and senile plaques. Among involved mechanisms, oxidative stress plays an important role in damaging cell components (e.g., proteins, nucleic acids). In this study, different oxidized products of proteins and DNA were determined in the urine samples from mild cognitive impairment due to AD patients (n = 53) and healthy controls (n = 27) by means of ultra-performance liquid chromatography-tandem mass spectrometry analysis. A multivariate model developed by partial least squares generated a diagnostic model for AD with an AUC-ROC (area under the curve-receiver operating characteristic) of 0.843. From the studied analytes, 8-OHdG (8-hydroxy-2’-deoxyguanosine) and the ratio 8-OHdG/2dG (2’-deoxyguanosine) were able to distinguish between AD and healthy participants, showing statistically significant differences between groups, postulating DNA oxidation as a molecular pathway involved in early AD.
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35
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IL-6 deficiency attenuates p53 protein accumulation in aged male mouse hippocampus. Biogerontology 2019; 21:29-43. [PMID: 31598806 PMCID: PMC6942598 DOI: 10.1007/s10522-019-09841-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 09/30/2019] [Indexed: 12/18/2022]
Abstract
Our earlier studies demonstrated slower age-related memory decline in IL-6-deficient than in control mice. Therefore, in the present study we evaluated the effect of IL-6 deficiency and aging on expression of p53, connected with accumulation of age-related cellular damages, in hippocampus of 4- and 24-month-old IL-6-deficient C57BL/6J (IL-6KO) and wild type control (WT) mice. The accumulation of p53 protein in hippocampus of aged IL-6KO mice was significantly lower than in aged WT ones, while p53 mRNA level was significantly higher in IL-6-deficient mice, what indicates that the effect was independent on p53 transcription. Presence of few apoptotic cells in hippocampal dentate gyrus and lack of changes in levels of pro-apoptotic Bax, antiapoptotic Bcl-2, as well as in p21 protein in aged animals of both genotypes, points to low transcriptional activity of p53, especially in aged WT mice. Because the amount of p53 protein did not correlate with the level of Mdm2 protein, its main negative regulator, other than Mdm2-dependent mechanism was involved in p53 build-up. Significantly higher mRNA levels of autophagy-associated genes: Pten, Tsc2, and Dram1 in IL-6KO mice, in conjunction with significantly lower amount of Bcl-2 protein in 4-month-old IL-6KO mice, suggests that lack of IL-6/STAT3/Bcl-2 signaling could account for better autophagy performance in these mice, preventing excessive accumulation of proteins. Taken together, attenuated p53 protein build-up, absence of enhanced apoptosis, and transcriptional up-regulation of autophagy-associated genes imply that IL-6 deficiency may protect hippocampus from age-related accumulation of cellular damages.
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36
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Bialuk I, Jakubów P, Winnicka MM. Significance of IL-6 Deficiency in Recognition Memory in Young Adult and Aged Mice. Behav Genet 2019; 49:415-423. [PMID: 31129771 PMCID: PMC6554246 DOI: 10.1007/s10519-019-09959-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 05/13/2019] [Indexed: 02/06/2023]
Abstract
Chronic peripheral elevation of interleukin 6 (IL-6) in humans is associated with cognitive deficits. 4- and 24-month-old IL-6-deficient C57BL/6J (IL-6KO) and reference wild-type (WT) mice were tested in an object recognition test. Discrimination ratios and recognition indexes were significantly lower in 4-month-old IL-6KO and in 24-month-old WT mice vs 4-month-old WT animals. Their discrimination ratios had negative values and recognition indexes were below 50% indicating inability to differentiate the novel from the familiar object after 1-hour delay. In 24-month-old IL-6KO mice recognition index reached 53.17% indicating that their recognition memory was not worsened with age in comparison with younger IL-6-deficient animals. Results of holeboard and elevated plus maze indicated that this effect was memory specific. Inborn IL-6 deficiency attenuated recognition memory in 4-month-old mice and did not altered recognition memory in aged animals. IL-6 signalling may constitute a target for development of the protection against memory disturbances connected with IL-6 overexpression.
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Affiliation(s)
- Izabela Bialuk
- Department of General and Experimental Pathology, Medical University of Białystok, Mickiewicza 2c, 15-222, Białystok, Poland.
| | - Piotr Jakubów
- Department of General and Experimental Pathology, Medical University of Białystok, Mickiewicza 2c, 15-222, Białystok, Poland
| | - Maria Małgorzata Winnicka
- Department of General and Experimental Pathology, Medical University of Białystok, Mickiewicza 2c, 15-222, Białystok, Poland
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Observational study of long-term persistent elevation of neurodegeneration markers after cardiac surgery. Sci Rep 2019; 9:7177. [PMID: 31073130 PMCID: PMC6509119 DOI: 10.1038/s41598-019-42351-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 03/11/2019] [Indexed: 12/17/2022] Open
Abstract
Surgery and anesthesia induce inflammatory changes in the central nervous system, which ultimately lead to neuronal damage concomitant with an increase in the level of neurodegeneration markers. Despite some experimental data showing prolonged activation of the immune system post-surgery, no study has determined the extent of long-term elevation of neurodegeneration markers. The purpose of this study was to investigate the serum levels of tau protein, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light (NF-L), and glial fibrillary acidic protein (GFAP) after elective cardiac surgery with the implementation of cardiopulmonary bypass (CPB). The serum levels of these markers from 30 patients were compared longitudinally to the baseline (pre-surgery or t0), at 24 hours (t+24), at 7 days (t+7d), and at 3 months (t+3m). The secondary outcome was the production of macrophage-colony stimulating factor (M-CSF) and tumor necrosis factor-α (TNF-α) in vitro by isolated monocytes in response to lipopolysaccharide (LPS) as the measure of immune system activation. The tertiary outcome was the serum level of C-reactive protein (CRP), serum amyloid P (SAP), and α-2-macroglobulin (A2M). Serum levels of tau protein increased 24 hours after surgery (p = 0.0015) and remained elevated at 7 days (p = 0.0017) and three months (p = 0.036). Serum levels of UCH-L1 peaked at 24 hours (p = 0.00055) and normalized at 3 months. In vitro secretion of M-CSF by LPS-stimulated peripheral monocytes, but not TNFα, correlated highly (r = 0.58; p = 0.04) with persistent elevation of serum tau levels at 3 months. The serum CRP and SAP increases correlated with tau post-CPB levels significantly at 3 months. We demonstrated that elevation of serum tau levels at 24 hours, 7 days, and 3 months after heart surgery is concomitant with some traits of inflammation after CPB. The elevation of tau several weeks into recovery is significantly longer than expected.
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38
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Pan H, Huang X, Li F, Ren M, Zhang J, Xu M, Wu M. Association among plasma lactate, systemic inflammation, and mild cognitive impairment: a community-based study. Neurol Sci 2019; 40:1667-1673. [DOI: 10.1007/s10072-019-03900-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 04/12/2019] [Indexed: 12/15/2022]
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Tsai CL, Pai MC, Ukropec J, Ukropcová B. Distinctive Effects of Aerobic and Resistance Exercise Modes on Neurocognitive and Biochemical Changes in Individuals with Mild Cognitive Impairment. Curr Alzheimer Res 2019; 16:316-332. [DOI: 10.2174/1567205016666190228125429] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/02/2018] [Accepted: 02/04/2019] [Indexed: 01/01/2023]
Abstract
Background:
Decreased levels of the neuroprotective growth factors, low-grade inflammation, and
reduced neurocognitive functions during aging are associated with neurodegenerative diseases, such as Alzheimer’s
disease. Physical exercise modifies these disadvantageous phenomena while a sedentary lifestyle
promotes them.
Purpose:
The purposes of the present study included investigating whether both aerobic and resistance exercise
produce divergent effects on the neuroprotective growth factors, inflammatory cytokines, and neurocognitive
performance, and further exploring whether changes in the levels of these molecular biomarkers are associated
with alterations in neurocognitive performance.
Methods:
Fifty-five older adults with amnestic MCI (aMCI) were recruited and randomly assigned to an aerobic
exercise (AE) group, a resistance exercise (RE) group, or a control group. The assessment included neurocognitive
measures [e.g., behavior and event-related potential (ERP)] during a task-switching paradigm, as
well as circulating neuroprotective growth factors (e.g., BDNF, IGF-1, VEGF, and FGF-2) and inflammatory
cytokine (e.g., TNF-α, IL-1β, IL-6, IL-8, and IL-15) levels at baseline and after either a 16-week aerobic or
resistance exercise intervention program or a control period.
Results:
Aerobic and resistance exercise could effectively partially facilitate neurocognitive performance [e.g.,
accuracy rates (ARs), reaction times during the heterogeneous condition, global switching cost, and ERP P3
amplitude] when the participants performed the task switching paradigm although the ERP P2 components and
P3 latency could not be changed. In terms of the circulating molecular biomarkers, the 16-week exercise interventions
did not change some parameters (e.g., leptin, VEGF, FGF-2, IL-1β, IL-6, and IL-8). However, the
peripheral serum BDNF level was significantly increased, and the levels of insulin, TNF-α, and IL-15 levels
were significantly decreased in the AE group, whereas the RE group showed significantly increased IGF-1
levels and decreased IL-15 levels. The relationships between the changes in neurocognitive performance (AR
and P3 amplitudes) and the changes in the levels of neurotrophins (BDNF and IGF-1)/inflammatory cytokines
(TNF-α) only approached significance.
Conclusion:
These findings suggested that in older adults with aMCI, not only aerobic but also resistance exercise
is effective with regard to increasing neurotrophins, reducing some inflammatory cytokines, and facilitating
neurocognitive performance. However, the aerobic and resistance exercise modes likely employed divergent
molecular mechanisms on neurocognitive facilitation.
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Affiliation(s)
- Chia-Liang Tsai
- Institute of Physical Education, Health and Leisure Studies, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan
| | - Ming-Chyi Pai
- Division of Behavioral Neurology, Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138, Sheng Li Road, Tainan, 704, Taiwan
| | - Jozef Ukropec
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Slovakia, Dubravska cesta 9, 84505 Bratislava, Slovakia
| | - Barbara Ukropcová
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Slovakia, Dubravska cesta 9, 84505 Bratislava, Slovakia
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40
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Deveci E, Kocacenk T, Şahan E, Yılmaz O, Öztürk A, Kırpınar İ. Oxidative stress and inflammatory response in patients with psoriasis; is there any relationship with psychiatric comorbidity and cognitive functions? PSYCHIAT CLIN PSYCH 2019. [DOI: 10.1080/24750573.2019.1589176] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Affiliation(s)
- Erdem Deveci
- Department of Psychiatry, Bezmialem Vakif University, Istanbul, Turkey
| | - Tuba Kocacenk
- Abant İzzet Baysal Üniversitesi İzzet Baysal Ruh Sağlığı Ve Hastalıkları Eğitim Ve Araştırma, Hastanesi, Bolu, Turkey
| | - Ebru Şahan
- Department of Psychiatry, Bezmialem Vakif University, Istanbul, Turkey
| | - Onur Yılmaz
- Department of Psychiatry, Bezmialem Vakif University, Istanbul, Turkey
| | - Ahmet Öztürk
- Department of Psychiatry, Bezmialem Vakif University, Istanbul, Turkey
| | - İsmet Kırpınar
- Department of Psychiatry, Bezmialem Vakif University, Istanbul, Turkey
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41
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Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer's disease. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2018; 4:575-590. [PMID: 30406177 PMCID: PMC6214864 DOI: 10.1016/j.trci.2018.06.014] [Citation(s) in RCA: 1406] [Impact Index Per Article: 200.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia-related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.
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Affiliation(s)
- Jefferson W. Kinney
- Department of Psychology, University of Nevada Las Vegas, Las Vegas, NV, USA
| | - Shane M. Bemiller
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andrew S. Murtishaw
- Department of Psychology, University of Nevada Las Vegas, Las Vegas, NV, USA
| | - Amanda M. Leisgang
- Department of Psychology, University of Nevada Las Vegas, Las Vegas, NV, USA
| | - Arnold M. Salazar
- Department of Psychology, University of Nevada Las Vegas, Las Vegas, NV, USA
| | - Bruce T. Lamb
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
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Abstract
Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) are involved in the pathogenesis of Alzheimer's disease (AD), which is characterized by the accumulation of β-amyloid protein (Aβ) and tau hyperphosphorylation. However, the gaps in our knowledge of the roles of COX-2 and PGs in AD have not been filled. Here, we summarized the literature showing that COX-2 dysregulation obviously influences abnormal cleavage of β-amyloid precursor protein, aggregation and deposition of Aβ in β-amyloid plaques and the inclusion of phosphorylated tau in neurofibrillary tangles. Neuroinflammation, oxidative stress, synaptic plasticity, neurotoxicity, autophagy, and apoptosis have been assessed to elucidate the mechanisms of COX-2 regulation of AD. Notably, an imbalance of these factors ultimately produces cognitive decline. The current review substantiates our understanding of the mechanisms of COX-2-induced AD and establishes foundations for the design of feasible therapeutic strategies to treat AD.-Guan, P.-P., Wang, P. Integrated communications between cyclooxygenase-2 and Alzheimer's disease.
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Affiliation(s)
- Pei-Pei Guan
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Pu Wang
- College of Life and Health Sciences, Northeastern University, Shenyang, China
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Casati M, Ferri E, Gussago C, Mazzola P, Abbate C, Bellelli G, Mari D, Cesari M, Arosio B. Increased expression of TREM2 in peripheral cells from mild cognitive impairment patients who progress into Alzheimer's disease. Eur J Neurol 2018; 25:805-810. [PMID: 29377401 DOI: 10.1111/ene.13583] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 01/19/2018] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND PURPOSE Neuroinflammation plays a role in the aetiopathogenesis of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2), a cell surface receptor of the immunoglobulin superfamily, seems to have protective anti-inflammatory activity in AD. METHODS Triggering receptor expressed on myeloid cells 2 expression was analysed in peripheral blood mononuclear cells from healthy subjects (CT) and from patients with either AD or mild cognitive impairment (MCI). MCI patients were re-evaluated at a 2-year follow-up to investigate their progression to AD (MCI-AD) or lack thereof (MCI-MCI). RESULTS Triggering receptor expressed on myeloid cells 2 gene expression was higher in AD than CT patients, but was highest in MCI. At recruitment TREM2 levels were higher in MCI-AD than in MCI-MCI, and in MCI-AD were higher initially than at follow-up. TREM2 displayed a moderate degree of sensitivity and specificity for identifying MCI-AD in all MCI patients. Our data showed higher TREM2 levels in allele ε4 of apolipoprotein E (ApoE ε4) carriers than non-carriers in MCI and particularly in MCI-AD. CONCLUSIONS These data seem to confirm the protective role of TREM2 in the pre-clinical stage of AD. Upregulation of TREM2 in MCI-AD could be a mechanism to counteract the activation of neuroinflammatory processes. It is possible that TREM2 and ApoE ε4 interact synergistically in the pre-clinical stage of AD. Therefore, TREM2 may be useful as an early peripheral biomarker for the development of AD.
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Affiliation(s)
- M Casati
- Geriatric Unit, Department of Medical Sciences and Community Health, University of Milan, Milan, Italy.,Nutritional Sciences, University of Milan, Milan, Italy
| | - E Ferri
- Geriatric Unit, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - C Gussago
- Geriatric Unit, Department of Medical Sciences and Community Health, University of Milan, Milan, Italy
| | - P Mazzola
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Acute Geriatrics Unit, San Gerardo Hospital ASST Monza, Monza, Italy.,NeuroMI Milan Center for Neuroscience, Clinical Neurosciences research area, Milano, Italy
| | - C Abbate
- Geriatric Unit, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - G Bellelli
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,Acute Geriatrics Unit, San Gerardo Hospital ASST Monza, Monza, Italy.,NeuroMI Milan Center for Neuroscience, Clinical Neurosciences research area, Milano, Italy
| | - D Mari
- Geriatric Unit, Department of Medical Sciences and Community Health, University of Milan, Milan, Italy.,Geriatric Unit, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - M Cesari
- Geriatric Unit, Department of Medical Sciences and Community Health, University of Milan, Milan, Italy.,Geriatric Unit, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - B Arosio
- Geriatric Unit, Department of Medical Sciences and Community Health, University of Milan, Milan, Italy.,Geriatric Unit, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
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44
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Reddan JM, White DJ, Macpherson H, Scholey A, Pipingas A. Glycerophospholipid Supplementation as a Potential Intervention for Supporting Cerebral Structure in Older Adults. Front Aging Neurosci 2018; 10:49. [PMID: 29563868 PMCID: PMC5845902 DOI: 10.3389/fnagi.2018.00049] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 02/15/2018] [Indexed: 01/13/2023] Open
Abstract
Modifying nutritional intake through supplementation may be efficacious for altering the trajectory of cerebral structural decline evident with increasing age. To date, there have been a number of clinical trials in older adults whereby chronic supplementation with B vitamins, omega-3 fatty acids, or resveratrol, has been observed to either slow the rate of decline or repair cerebral tissue. There is also some evidence from animal studies indicating that supplementation with glycerophospholipids (GPL) may benefit cerebral structure, though these effects have not yet been investigated in adult humans. Despite this paucity of research, there are a number of factors predicting poorer cerebral structure in older humans, which GPL supplementation appears to beneficially modify or protect against. These include elevated concentrations of homocysteine, unbalanced activity of reactive oxygen species both increasing the risk of oxidative stress, increased concentrations of pro-inflammatory messengers, as well as poorer cardio- and cerebrovascular function. As such, it is hypothesized that GPL supplementation will support cerebral structure in older adults. These cerebral effects may influence cognitive function. The current review aims to provide a theoretical basis for future clinical trials investigating the effects of GPL supplementation on cerebral structural integrity in older adults.
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Affiliation(s)
- Jeffery M Reddan
- Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, VIC, Australia
| | - David J White
- Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, VIC, Australia
| | - Helen Macpherson
- Institute for Physical Activity and Nutrition, Deakin University, Melbourne, VIC, Australia
| | - Andrew Scholey
- Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, VIC, Australia
| | - Andrew Pipingas
- Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, VIC, Australia
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45
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Boyko AA, Troyanova NI, Kovalenko EI, Sapozhnikov AM. Similarity and Differences in Inflammation-Related Characteristics of the Peripheral Immune System of Patients with Parkinson's and Alzheimer's Diseases. Int J Mol Sci 2017; 18:ijms18122633. [PMID: 29211044 PMCID: PMC5751236 DOI: 10.3390/ijms18122633] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 11/21/2017] [Accepted: 12/01/2017] [Indexed: 12/14/2022] Open
Abstract
Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common age-related neurodegenerative disorders. Both diseases are characterized by chronic inflammation in the brain-neuroinflammation. The first signs of PD and AD are most often manifested in old age, in which the immune system is usually characterized by chronic inflammation, so-called "inflammaging" In recent years, there is growing evidence that pathogenesis of these diseases is connected with both regional and peripheral immune processes. Currently, the association of clinical signs of PD and AD with different characteristics of patient immune status is actively being researched. In this mini-review we compare the association of PD and AD alterations of a number of immune system parameters connected with the process of inflammation.
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Affiliation(s)
- Anna A Boyko
- Laboratory of Cell Interactions, Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.
| | - Natalya I Troyanova
- Laboratory of Cell Interactions, Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.
| | - Elena I Kovalenko
- Laboratory of Cell Interactions, Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.
| | - Alexander M Sapozhnikov
- Laboratory of Cell Interactions, Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia.
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46
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Elaskalani O, Khan I, Morici M, Matthysen C, Sabale M, Martins RN, Verdile G, Metharom P. Oligomeric and fibrillar amyloid beta 42 induce platelet aggregation partially through GPVI. Platelets 2017; 29:415-420. [PMID: 29206067 DOI: 10.1080/09537104.2017.1401057] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The effects of the Alzheimer's disease (AD)-associated Amyloid-β (Aβ) peptides on platelet aggregation have been previously assessed, but most of these studies focused on Aβ40 species. It also remains to be determined which distinct forms of Aβ peptides exert differential effects on platelets. In AD, oligomeric Aβ42 species is widely thought to be a major contributor to the disease pathogenesis. We, therefore, examine the ability of oligomeric and fibrillary Aβ42 to affect platelet aggregation. We show that both forms of Aβ42 induced significant platelet aggregation and that it is a novel ligand for the platelet receptor GPVI. Furthermore, a novel binding peptide that reduces the formation of soluble Aβ42 oligomers was effective at preventing Aβ42-dependent platelet aggregation. These results support a role for Aβ42 oligomers in platelet hyperactivity.
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Affiliation(s)
- O Elaskalani
- a School of Biomedical Sciences, Faculty of Health Sciences , Curtin Health Innovation Research Institute, Curtin University , Perth , Australia
| | - I Khan
- a School of Biomedical Sciences, Faculty of Health Sciences , Curtin Health Innovation Research Institute, Curtin University , Perth , Australia
| | - M Morici
- b School of Medical Sciences , Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University , Joondalup , WA , Australia
| | - C Matthysen
- a School of Biomedical Sciences, Faculty of Health Sciences , Curtin Health Innovation Research Institute, Curtin University , Perth , Australia
| | - M Sabale
- a School of Biomedical Sciences, Faculty of Health Sciences , Curtin Health Innovation Research Institute, Curtin University , Perth , Australia
| | - R N Martins
- a School of Biomedical Sciences, Faculty of Health Sciences , Curtin Health Innovation Research Institute, Curtin University , Perth , Australia.,c Department of Biomedical Sciences, Faculty of Medicine and Health Sciences , Macquarie University , NSW , Sydney , Australia
| | - G Verdile
- a School of Biomedical Sciences, Faculty of Health Sciences , Curtin Health Innovation Research Institute, Curtin University , Perth , Australia.,b School of Medical Sciences , Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University , Joondalup , WA , Australia.,d School of Psychiatry and Clinical Neurosciences , University of WA , Perth , Australia
| | - P Metharom
- e Faculty of Health Sciences , Curtin Health Innovation Research Institute, Curtin University , Perth , Australia
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47
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Immune and Imaging Correlates of Mild Cognitive Impairment Conversion to Alzheimer's Disease. Sci Rep 2017; 7:16760. [PMID: 29196629 PMCID: PMC5711836 DOI: 10.1038/s41598-017-16754-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 11/16/2017] [Indexed: 01/18/2023] Open
Abstract
Amnestic mild cognitive impairment (aMCI) conversion to Alzheimer’s disease (AD) is seen in a sizable portion of aMCI patients; correlates predicting such conversion are poorly defined but neuroinflammation and the reactivation of chronic viral infections are suspected to play a role in this phenomenon. We analyzed these aspects in two homogeneous groups of aMCI who did or did not convert to AD over a 24-months period. Results showed that at baseline in those aMCI individuals who did not convert to AD: 1) Aβ1-42 stimulated production of the pro-inflammatory cytokines IL6 and IL1β by CD14+ cells was significantly reduced (p = 0.01), 2) CD14+/IL-33+ cells were increased (p = 0.0004); 3) MFI of TLR8 and TLR9 was significantly increased, and 4) better preserved hippocampus volumes were observed and correlated with IL33+/CD14+ cells. Notably, Aβ1-42 stimulated production of the antiviral cytokine IFN-λ was increased as well in non-AD converters, although with a borderline statistical significance (p = 0.05). Data herein indicating that proinflammatory cytokines are reduced, whereas IFN-λ production and TLR8 and 9 MFI are augmented in those aMCI in whom AD conversion is not observed suggest that the ability to mount stronger antiviral response within an antiiflammatory milieu associates with lack of AD conversion.
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48
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Wojsiat J, Laskowska-Kaszub K, Mietelska-Porowska A, Wojda U. Search for Alzheimer's disease biomarkers in blood cells: hypotheses-driven approach. Biomark Med 2017; 11:917-931. [PMID: 28976776 DOI: 10.2217/bmm-2017-0041] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Current Alzheimer's disease (AD) diagnostics is based on cognitive testing, and detecting amyloid Aβ and τ pathology by brain imaging and assays of cerebrospinal fluid. However, biomarkers identifying complex pathways contributing to pathology are lacking, especially for early AD. Preferably, such biomarkers should be more cost-effective and present in easily available diagnostic tissues, such as blood. Here, we summarize the recent findings of potential early AD molecular diagnostic biomarkers in blood platelets, lymphocytes and erythrocytes. We review molecular alterations which refer to such main hypotheses of AD pathogenesis as amyloid cascade, oxidative and mitochondrial stress, inflammation and alterations in cell cycle regulatory molecules. The major advantage of such biomarkers is the potential ability to indicate individualized therapies in AD patients.
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Affiliation(s)
- Joanna Wojsiat
- Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Polish Academy of Science, Pasteur 3 St., 02-093 Warsaw, Poland
| | - Katarzyna Laskowska-Kaszub
- Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Polish Academy of Science, Pasteur 3 St., 02-093 Warsaw, Poland
| | - Anna Mietelska-Porowska
- Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Polish Academy of Science, Pasteur 3 St., 02-093 Warsaw, Poland
| | - Urszula Wojda
- Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology, Polish Academy of Science, Pasteur 3 St., 02-093 Warsaw, Poland
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49
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Rostami F, Javan M, Moghimi A, Haddad-Mashadrizeh A, Fereidoni M. Streptozotocin-induced hippocampal astrogliosis and insulin signaling malfunction as experimental scales for subclinical sporadic Alzheimer model. Life Sci 2017; 188:172-185. [PMID: 28867578 DOI: 10.1016/j.lfs.2017.08.025] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 08/23/2017] [Accepted: 08/26/2017] [Indexed: 11/15/2022]
Abstract
AIMS Insulin signaling malfunction has recently been suggested as a preliminary event involved in the etiology of Sporadic Alzheimer's disease (SAD). In order to develop insulin resistance-related SAD model, rats were treated with streptozotocin, intracerebroventricularly (icv-STZ). Nevertheless, given the lack of knowledge regarding sub-clinical stages of SAD, the current challenging issue is establishing a practical pre-clinical SAD model. Despite some proposed mechanisms, such as insulin malfunction, neuroinflammation, and gliosis, icv-STZ mechanism of action is not fully understood yet and Streptozotocin-induced rat model of Alzheimer has still major shortcomings. MAIN METHODS Using three STZ doses (0.5, 1, and 3mg/kg) and three testing time (short-term, medium-term and long-term), we sought the best dose of STZ in order to mimic the characteristic feature of sAD in rats. So, we conducted a series of fifteen-week follow-up cognitive and non-cognitive studies. Besides, IR, tau and ChAT mRNA levels were measured, along with histological analysis of astrocyte, dark neuron numbers, and pyramidal layer thickness, in order to compare the effects of different doses of icv-STZ. KEY FINDINGS STZ 3mg/kg caused cognitive and insulin signaling disturbance from the very first testing-time. STZ1-injected animals, however, showed an augmented hippocampal astrocyte numbers in a short time; they, also, were diagnosed with disturbed insulin signaling in medium-term post icv-STZ-injection. Moreover, behavioral, molecular and histological impairments induced by 0.5mg/kg icv-STZ were slowly progressing in comparison to high doses of STZ. SIGNIFICANCE STZ1 and 0.5mg/kg-treated animals are, respectively, suggested as a suitable experimental model of MCI, and sub-clinical stage.
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Affiliation(s)
- Farzaneh Rostami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mohammad Javan
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Moghimi
- Rayan Center for Neuroscience and Behavior, Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Aliakbar Haddad-Mashadrizeh
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran; Cell and Molecular Research group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Masoud Fereidoni
- Rayan Center for Neuroscience and Behavior, Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
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50
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Chen B, Zheng T, Qin L, Hu X, Zhang X, Liu Y, Liu H, Qin S, Li G, Li Q. Strong Association between Plasma Dipeptidyl Peptidase-4 Activity and Impaired Cognitive Function in Elderly Population with Normal Glucose Tolerance. Front Aging Neurosci 2017; 9:247. [PMID: 28798686 PMCID: PMC5526854 DOI: 10.3389/fnagi.2017.00247] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 07/14/2017] [Indexed: 12/20/2022] Open
Abstract
Objective: Inflammation, oxidative stress, and decreased glucagon-like peptide-1 (GLP-1) are risk factors for cognitive impairment. Dipeptidyl peptidase-4 (DPP4) was identified as a novel adipokine capable of enhancing these risk factors. Hence, we investigated the relationship between plasma DPP4 activity and impaired cognitive function in elderly Chinese population with normal glucose tolerance (NGT). Methods: We performed a cross-sectional study using data from 1229 elderly participants (60 years or older) in Guilin. Plasma DPP4 activity, oxidative stress parameters, fasting active GLP-1, and inflammatory markers were measured in all participants. Impaired cognitive function was diagnosed according to the National Institute on Aging-Alzheimer's Association workgroups criteria. Results: Participants in the upper quartile of plasma DPP4 activity had higher C-reactive protein (CRP), interleukin-6 (IL-6), 8-iso-PGF2a, nitrotyrosine, and lower GLP-1 and Montreal Cognitive Assessment (MoCA) scores compared with those in the lowest quartile (P < 0.001). The odds ratios (ORs) for increased CRP, IL-6, 8-iso-PGF2a, nitrotyrosine, and decreased active GLP-1 were higher with increasing DPP4 quartiles after adjustment for confounders (all P < 0.001). In the highest DPP4 quartile, impaired cognitive function risk was higher (OR, 2.26; 95% confidence interval, 1.36-3.76) than in the lowest quartile after adjustment for potential confounders. The risk for impaired cognitive function increased more with higher levels of DPP4 activity, nitrotyrosine and 8-iso-PGF2a (P < 0.05), but not with higher IL-6, CRP or lower GLP-1. Conclusion: Plasma DPP4 activity is significantly and independently associated with impaired cognitive function, mainly executive, in elderly Chinese population with NGT. The underlying mechanisms for this association may be partly attributed to the effect of DPP4 on oxidative stress. Plasma DPP4 activity might serve as a risk biomarker or therapeutic target for the prevention and treatment of impaired cognitive function.
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Affiliation(s)
- Bo Chen
- Department of Human Anatomy, Southwest Medical UniversityLuzhou, China.,Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital of Southwest Medical UniversityLuzhou, China
| | - Tianpeng Zheng
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical UniversityGuilin, China.,Center of Diabetic Systems Medicine, Guilin Medical UniversityGuilin, China
| | - Linyuan Qin
- Department of Epidemiology and Health Statistics, Guilin Medical UniversityGuilin, China
| | - Xueping Hu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guilin Medical UniversityGuilin, China
| | - Xiaoxi Zhang
- Center of Diabetic Systems Medicine, Guilin Medical UniversityGuilin, China
| | - Yihong Liu
- Diabetic Centre of Control and Prevention, The People's Liberation Army 520 HospitalMianyang, China
| | - Hongbo Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical UniversityGuilin, China
| | - Shenghua Qin
- Medical Examination Center, Affiliated Hospital of Guilin Medical UniversityGuilin, China
| | - Gang Li
- Department of Psychiatry, Affiliated Hospital of Guilin Medical UniversityGuilin, China
| | - Qinghua Li
- Department of Psychiatry, Affiliated Hospital of Guilin Medical UniversityGuilin, China.,Department of Neurology, Affiliated Hospital of Guilin Medical UniversityGuilin, China
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