Amyloid plaque deposition accelerates tau propagation via activation of microglia in a humanized APP mouse model

Microglia have an emerging role in development of tau pathology after amyloid plaque deposition in Alzheimers disease, although it has not been definitively shown. We hypothesize that plaque-associated activated microglia accelerate tau propagation via enhanced phagocytosis and secretion of tau. Here we show that the injection of adeno-associated virus expressing P301L tau mutant into the medial entorhinal cortex (MEC) in humanized APPNL-G-F knock-in mice induces exacerbated tau propagation in the dentate gyrus compared to wild type mice. Depletion of microglia dramatically reduces accumulation of phosphorylated tau (pTau) in the dentate gyrus as well as an extracellular vesicle (EV) marker, Tumor susceptibility gene 101, co-localized in microglia. Mac2+ activated microglia secrete significantly more EVs compared to Mac2- microglia in APPNL-G-F mice in vivo when injected with lentivirus expressing EV reporter gene mEmerald-CD9, suggesting enhanced EV secretion by microglial activation. Our findings indicate that amyloid plaque-mediated acceleration of tau propagation is dependent on activated microglia, which show enhanced EV secretion in vivo.