Microglia Degrade Extracellular Tau Oligomers Deposits via Purinergic P2Y12-Driven Podosomes, Filopodia Formation and Induce Chemotaxis

Abstract

Tau is a microtubule-associated protein, which accumulates as neurofibrillary tangles and becomes deposited as plaques in the brain during Alzheimer’s disease (AD). Tau undergoes various post-translational modifications that lead to its self-oligomerization, aggregation, and subsequent escape from affected neurons. Tau oligomers are the most reactive species associated with neurotoxic and inflammatory activity. Microglia are the immune cells in the central nervous system, sense the extracellular presence of Tau via various cell surface receptors among which purinergic P2Y12 receptor can directly interact with Tau oligomers and mediates microglial chemotaxis via actin remodeling. The disease-associated microglia leads to impaired migration and expresses a reduced level of homeostatic genes such as P2Y12 while elevates the expression of phagocytic, reactive oxygen species, and pro-inflammatory cytokines. Extracellular Tau oligomers facilitated the microglial migration via Arp2-associated podosomes and filopodia formation through the activation of P2Y12 signaling. The Tau oligomers-induced the decoration of TKS5-associated podosomes clusters at microglial lamella in a time-dependent manner. Moreover, the P2Y12 receptor was evidenced to localize with the actin core of podosomes and in filopodia for Tau-deposits degradation. While the blockage of P2Y12 signaling resulted in decreased microglial migration and reduced Tau-deposits degradation. Hence, the P2Y12 signaling mediated the formation of migratory actin structures like-podosomes and filopodia to exhibit chemotaxis and degrade Tau deposits. These beneficial roles of P2Y12 signaling in microglial chemotaxis, migratory actin network remodeling, and Tau clearance can be intervened as a therapeutic targets in AD.