Microglia Process α‐Synuclein Fibrils and Enhance their Pathogenicity in a TREM2‐Dependent Manner

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.