G-Protein coupled receptor-mediated internalization and endosomal sorting of Tau-GPCR complex in microglia.

Microglia are the resident immune cells of the central nervous system (CNS), which are in constant surveillance of the brain microenvironment to maintain tissue homeostasis. Microglia play significant role both in the physiological and pathological conditions of the brain. Alzheimer's Disease (AD) is a neurodegenerative disease that includes progressive dementia and cognitive deficits. The two main culprits of AD are extracellular amyloid-β plaques and neurofibrillary tangles formed by Tau protein. In AD brain, intrinsically disordered Tau undergoes rapid oligomerization and self-aggregates to form filamentous species. Clearance of these toxic species is mainly performed by microglia, which can sense through various receptors such as Toll-like receptors (TLRs), G-Protein coupled receptor (GPCRs), purinergic receptors, etc. One such receptor is P2Y12R, a purinergic receptor whose expression is restricted to microglia in CNS. In this review, we envisioned providing an insight into the involvement of P2Y12R, a purinergic cell surface receptor that facilitates the internalization of Tau along with the other mechanisms of Tau clearance in microglia. Exploring these receptors and elucidating the mechanisms underlying Tau transmission could pave the way for the development of innovative therapeutic approaches aimed at impeding the spread of Tau pathology in neurodegenerative diseases.