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

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.