Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils
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Le résumé fourni par la source
Abstract Microglia, the primary immune cells of the central nervous system, play a crucial role in maintaining brain homeostasis through phagocytosis of various substrates, including amyloid-β (Aβ) fibrils, a hallmark of Alzheimer disease (AD) pathology. However, the molecular mechanisms regulating microglial Aβ uptake remain poorly understood. Here, we identified GPR34, a Gi/o-coupled receptor highly expressed in microglia, as a novel regulator of fibrillar Aβ phagocytosis. Treatment with a selective GPR34 agonist, M1, specifically enhanced uptake of Aβ fibrils, but not its monomer or oligomer, in both mouse and human microglia. Mechanistically, M1 reduced intracellular cAMP levels, which inversely correlated with Aβ uptake activity. Importantly, a single intrahippocampal injection of M1 in an AD mouse model significantly increased microglial Aβ uptake in vivo. Furthermore, single-nucleus RNA-sequencing analysis of Japanese AD patient samples revealed a significant reduction of GPR34 expression in microglia from AD patients compared to controls. We also observed an age-dependent decline in microglial GPR34 expression in both human and mouse datasets, suggesting a potential contribution of GPR34 downregulation to age-related Aβ accumulation and AD risk. Collectively, our findings identify GPR34 as a promising target for modulating microglial Aβ clearance and highlight the therapeutic potential of GPR34 agonists in AD. Significance statement Alzheimer disease (AD) is characterized by amyloid-β (Aβ) accumulation in the brain. Microglia, the brain’s immune cells, play a crucial role in the metabolism of Aβ. We discovered that activating the microglial receptor GPR34 with a selective agonist enhances the phagocytosis of Aβ fibrils, a key pathogenic form of Aβ. Importantly, GPR34 expression decreases with aging and AD progression, potentially contributing to impaired Aβ clearance. Our findings highlight GPR34 as a promising therapeutic target for AD, as boosting its activity could promote Aβ clearance and slow disease progression. This study provides valuable insights into microglial function in AD and offers a novel strategy for developing disease-modifying therapies.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils
- Date Crossref
- 09/05/2024
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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The University of Tokyo pays non établi dans la noticeUniversité ou école supérieure
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Keio University Department of Physiology pays non établi dans la noticeUniversité ou école supérieure
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Niigata University Department of Molecular Genetics pays non établi dans la noticeUniversité ou école supérieure
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Tokyo Metropolitan Institute of Gerontology pays non établi dans la noticeStructure de recherche
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Nagoya City University Department of Neurocognitive Science pays non établi dans la noticeUniversité ou école supérieure
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RIKEN Center for Brain Science pays non établi dans la noticeStructure de recherche
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Tohoku University Department of Experimental Immunology pays non établi dans la noticeUniversité ou école supérieure
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Graduate School of Pharmaceutical Sciences Laboratory of Neuropathology and Neuroscience pays non établi dans la noticeUniversité ou école supérieure
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Tokyo Metropolitan Institute for Geriatrics and Gerontology Department of Neuropathology (the Brain Bank for Aging Research) pays non établi dans la noticeStructure de recherche
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Laboratory for Proteolytic Neuroscience pays non établi dans la noticeStructure de recherche
The University of Tokyo, Department of Physiology — Keio University et Department of Molecular Genetics — Niigata University, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.