Physical Exercise Decreases Complement-Mediated Synaptic Loss and Protects Against Cognitive Impairment by Inhibiting Microglial Tmem9-ATP6V0D1 in Alzheimer's Disease

作     者：Li, Shiyin Li, Mingyue Li, Ge Li, Lili Yang, Xiaofeng Zuo, Zejie Zhang, Liying Hu, Xiquan He, Xiaofei 

作者机构：Sun Yat Sen Univ Affiliated Hosp 3 Dept Rehabil Med Guangzhou Guangdong Peoples R China Guangdong Lab Anim Monitoring Inst Guangdong Prov Key Lab Lab Anim Guangzhou Guangdong Peoples R China 

出 版 物：《AGING CELL》 (Aging Cell)

年 卷 期：2025年第24卷第5期

页      面：e14496页

核心收录：

基　　金：National Key Research and Development Program of China 

主　　题：Alzheimer's disease complement activation microglia physical exercise Tmem9 

摘      要：Physical exercise is known to slow synaptic neurodegeneration and cognitive aging in Alzheimer s disease (AD). The benefits of physical exercise are related to reduced amyloid beta (A beta) deposition and increased synaptic plasticity. Yet little is known about the mechanisms that mediate these effects. Here, we show that physical exercise down-regulated the microglial Tmem9 protein, inhibited C1q activation, and decreased C1q-dependent microglial synapse engulfment, eventually ameliorating cognitive impairment in 5xFAD mice. Furthermore, using oA beta cultured-BV2 in vitro, we show that downregulation of microglial Tmem9 was sufficient to restrain complement activity and decrease microglia-mediated synaptic loss, whereas overexpression of microglial Tmem9 tended to promote complement activation and induced synaptic loss, abolishing exercise-associated protection. Finally, we show that microglial Tmem9 contributed to complement activation by regulating ATP6V0D1, a vesicular (H+) ATP-dependent proton pump (V-ATPase) subunit that regulates V-ATPase assembly. Together, our results demonstrate that exercise is a potential treatment for AD patients. In an AD mouse model, it decreased the levels of microglial Tmem9 to inhibit the activation of complement, alleviated complement-dependent synaptic loss, and eventually ameliorated emotional and cognitive disorders.