Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils
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Le résumé fourni par la source
BACKGROUND: Microglia play a crucial role in brain homeostasis through phagocytosis of amyloid-β (Aβ) fibrils, a hallmark of Alzheimer disease (AD) pathology. The balance between Aβ production and clearance is critical for AD pathogenesis, with impaired clearance mechanisms potentially contributing to disease progression. G-protein coupled receptor 34 (GPR34), a microglia-enriched Gi/o-coupled receptor, is highly expressed in homeostatic microglia and may regulate phagocytic functions, yet its role in Aβ clearance remains poorly understood. METHODS: Using flow cytometry-based assays, we investigated the effect of a selective GPR34 agonist (M1) on Aβ uptake in mouse primary microglia and human induced pluripotent stem cell-derived microglia. We evaluated uptake specificity across different Aβ species and phagocytic substrates, and measured intracellular cyclic adenosine monophosphate (cAMP) levels to determine the signaling mechanism. We performed in vivo studies using human amyloid precursor protein knock-in mice with intrahippocampal M1 injections. Additionally, we analyzed GPR34 expression in Japanese AD patient brain samples using single-nucleus RNA sequencing and examined age-dependent expression changes across multiple datasets. RESULTS: M1 specifically enhanced uptake of Aβ fibrils through reduction of intracellular cAMP levels, without affecting monomeric or oligomeric Aβ internalization. Gpr34 knockdown experiments confirmed GPR34 as the molecular target of M1. An intrahippocampal injection of M1 significantly increased microglial Aβ uptake in vivo, an effect that required functional TREM2 signaling. GPR34 expression was significantly reduced in microglia from AD patients and showed age-dependent decline in both humans and mice. CONCLUSIONS: Our findings identify GPR34 as a promising therapeutic target for enhancing microglial Aβ clearance and highlight the potential of GPR34 agonists for AD treatment. The age-dependent decline in GPR34 expression may contribute to reduced Aβ clearance efficiency in aging brains, exacerbating amyloid accumulation. Pharmacological activation of GPR34 represents a novel strategy to counteract impaired Aβ clearance in both aging and AD brains, potentially modifying disease progression through enhancement of microglial phagocytic function.
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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
- 20/11/2025
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
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 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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Graduate School of Medical Science Department of Neurocognitive Science pays non établi dans la noticeUniversité ou école supérieure
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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 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.