ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
Microglia Process α-Synuclein Fibrils and Enhance their Pathogenicity in a TREM2-Dependent Manner.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Research on Parkinson's disease immunotherapy: a bibliometric analysis via multiple databases.Frontiers in immunology · 2025Pooled it
- Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.Molecular neurobiology · 2026Review
- Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.Neural regeneration research · 2026Article
- TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.Cell communication and signaling : CCS · 2026Review
- Microglia and neuroinflammation: function, heterogeneity, and crosstalk.Cellular & molecular immunology · 2026Review
- Microglial ITAM & ITIM Signaling in Neurodegenerative Disease and Brain Aging.Journal of molecular biology · 2026Review
- Microglial Nrf2 Activation Orchestrates Ferroptosis Inhibition and α-Synuclein Clearance in Parkinson's Disease.International journal of molecular sciences · 2026Article
- Microglial Innate Immune Memory: Implications and Research Advances in Central Nervous System Disorders.Current issues in molecular biology · 2026Review
- Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Targeting Microglial CD49a Inhibits Neuroinflammation and Demonstrates Therapeutic Potential for Parkinson's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Parkinson's disease: spatiotemporal regulation and therapeutic prospects of TREM2-mediated microglial responses.NPJ Parkinson's disease · 2026Review
- α2-3-sialylated glycosphingolipids in neuroinflammation, immunity, and programmed cell death: mechanistic evidence and context-dependent regulation: a comprehensive review.Frontiers in immunology · 2026Review
- Microglia heterogeneity and therapeutic strategies in Parkinson's disease.Frontiers in immunology · 2026Review
- Human microglia reduce alpha-synuclein aggregation and are neuroprotective in adult mouse brain.Brain, behavior, and immunity · 2025Article
- A New Driver of Parkinson's Disease: FAM171A2 Facilitates α-Synuclein Uptake and Spread.Neuroscience bulletin · 2025Article
- Cerebrospinal fluid sTREM2 mediates the associations of α-synuclein with tau pathology in older adults without dementia: two population-based study.Journal of translational medicine · 2025Article
- α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges.International journal of molecular sciences · 2025Review
- Microglia Process α-Synuclein Fibrils and Enhance their Pathogenicity in a TREM2-Dependent Manner.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
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Authors and funding
15 authors.
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Abstract
Parkinson's disease (PD) is characterized by the deposition of misfolded α-synuclein (α-syn) in the brain. Converging evidence indicates that the intracellular transmission and subsequent templated amplification of α-syn are involved in the onset and progression of PD. However, the molecular mechanisms underlying the cell-to-cell transmission of pathological α-syn remain poorly understood. Microglia is highly activated in the brains of PD patients. Here, it is shown that depletion of microglia slows the spread of pathological α-syn pathology in mice injected with α-syn fibrils. Microglia phagocytose α-syn fibrils and transform them into more toxic species. The phagocytosis of α-syn fibrils by microglia is partially mediated by triggering a receptor expressed on myeloid cells 2 (TREM2), a transmembrane protein expressed on the surface of microglia. The endocytosed α-syn fibrils are then cleaved by the lysosomal proteinase asparagine endopeptidase (AEP) to generate truncated α-syn 1-103 fibrils with enhanced seeding activity. Knockout of TREM2 and AEP impedes the endocytosis and cleavage of α-syn fibrils, respectively. The results demonstrate that TREM2-mediated phagocytosis of α-syn fibrils by microglia and subsequent AEP-mediated cleavage of α-syn fibrils contribute to the spread of α-syn in the brain. Blocking either of these two steps attenuates the progression of α-syn pathology.
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