Complement receptor 4 mediates the clearance of extracellular tau fibrils by microglia

Abstract

Abstract Background Abnormal accumulation of misfolded tau aggregates is a key pathological hallmark of various tauopathies including Alzheimer’s disease. Tau pathology shows disease-specific spatiotemporal propagation through intercellular transmission, which is closely correlated with the progression of clinical manifestations. Therefore, identifying the molecular mechanisms preventing tau propagation is critical to develop therapeutic strategy for tauopathies. The various innate immune receptors, such as complement receptor 3 (CR3) and complement receptor 4 (CR4), have been reported to play a critical role in the clearance of various extracellular toxic molecules by microglia. However, their role in tau clearance has not been studied yet. In this study, we investigated the role of CR3 and CR4 in regulating extracellular tau clearance. Results Here, we identified that CR4 selectively binds to tau fibrils but not to tau monomers, whereas CR3 does not bind to any of them. We further demonstrated that inhibiting CR4 significantly reduces the uptake of tau fibrils by microglial BV2 cells, whereas CR3 does not affect the uptake of tau fibrils. We further demonstrated that inhibiting CR4 suppresses the clearance extracellular tau fibrils without altering the extracellular degradation of tau fibrils in the culture media. Moreover, conditioned media from CR4-silenced BV2 culture incubated with tau fibrils retain more seeding capacity than controls. Conclusion Taken together, our data strongly support that CR4 is a novel receptor for the clearance of tau fibril in microglia and may represent a novel therapeutic target for tauopathy.