Open AccessMicroglial Calhm2 regulates neuroinflammation and contributes to Alzheimer’s disease pathology
Author(s) -
Jinbo Cheng,
Yuan Dong,
Jun Ma,
RuiYuan Pan,
Yuhe Liao,
Xu Kong,
Xiaoheng Li,
Shuoshuo Li,
Ping-Fang Chen,
Liang Wang,
Ye Yu,
Zengqiang Yuan
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abe3600
Subject(s) - neuroinflammation , microglia , conditional gene knockout , knockout mouse , proinflammatory cytokine , inflammation , neurodegeneration , neuroscience , alzheimer's disease , medicine , biology , immunology , pathology , disease , receptor , phenotype , gene , biochemistry
Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. Neuronal calcium dysfunction and microglial-mediated neuroinflammation are closely associated with the development of AD. However, it remains unknown whether calcium dysfunction contributes to microglial activation and, in turn, AD pathology in vivo. In this study, we demonstrated that the expression of calcium homeostasis modulator family protein 2 (Calhm2) is increased in an AD mouse model. In 5×FAD mice carrying five familial AD gene mutations, both conventional knockout of Calhm2 and conditional microglial knockout of Calhm2 significantly reduced amyloid β deposition, neuroinflammation, and cognitive impairments. Mechanistically, knockout of Calhm2 inhibited microglial proinflammatory activity but increased phagocytic activity, leading to restoration of the balance between inflammation and phagocytosis. In addition, knockout of Calhm2 reduced acute LPS-induced neuroinflammation. These results highlight an important role for Calhm2 in microglial activation and provide a potential therapeutic target for diseases related to microglia-mediated neuroinflammation.