Microglial Calhm2 regulates neuroinflammation and contributes to Alzheimer's disease pathology

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 5xFAD mice carrying five familial AD gene mutations, both conventional knockout of Calhm2 and conditional microglial knockout of Calhm2 significantly reduced amyloid beta 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.

Automated summary

This study showed that increased expression of Calhm2 in an AD mouse model, and its knockout significantly reduced amyloid beta deposition, neuroinflammation, and cognitive impairments. Knockout of Calhm2 inhibited microglial proinflammatory activity but increased phagocytic activity, leading to the restoration of the balance between inflammation and phagocytosis.