Modulation of Ryanodine Receptors on Microglial Ramification, Migration, and Phagocytosis in an Alzheimer’s Disease Mouse Model
Yulin Ouyang1,2 · Zihao Chen1 · Qiang Huang1 · Hai Zhang1 · Haolin Song1 · Xinnian Wang1 · Wenxiu Dong1 · Yong Tang1 · Najeebullah Shah3 · Shimin Shuai3 · Yang Zhan1,4
1 Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
2 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China
3 Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
4 Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China
Abstract
Microglial functions are linked to Ca2+ signaling, with endoplasmic reticulum (ER) calcium stores playing a crucial role. Microglial abnormality is a hallmark of Alzheimer’s disease (AD), but how ER Ca2+ receptors 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 Ca2+ transients in controls and normalized Ca2+ transients 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 Ca2+ receptors in both homeostatic and AD microglia, providing insights into microglial Ca2+ malfunctions in AD.
Keywords
Microglia; Alzheimer’s disease; ER calcium signaling; Ryanodine receptor; ORAI
