Modulation of Ryanodine Receptors on Microglial Ramification, Migration, and Phagocytosis in an Alzheimer's Disease Mouse Model.

Abstract

Microglial functions are linked to Casignaling, with endoplasmic reticulum (ER) calcium stores playing a crucial role. Microglial abnormality is a hallmark of Alzheimer's disease (AD), but how ER Careceptors regulate microglial functions under physiological and AD conditions remains unclear. We found reduced ryanodine receptor 2 (Ryr2) expression in microglia from an AD mouse model. Modulation of RyR2 using S107, a RyR-Calstabin stabilizer, blunted spontaneous Catransients in controls and normalized Catransients in AD mice. S107 enhanced ATP-induced migration and phagocytosis while reducing ramification in control microglia; however, these effects were absent in AD microglia. Our findings indicate that RyR2 stabilization promotes an activation state shift in control microglia, a mechanism impaired in AD. These results highlight the role of ER Careceptors in both homeostatic and AD microglia, providing insights into microglial Camalfunctions in AD.