Microglial Calhm2 regulates neuroinflammation and contributes to Alzheimer's disease pathology
Jinbo Cheng1,2, Yuan Dong3, Jun Ma2
1Center on Translational Neuroscience, College of Life and Environmental Science, Minzu University of China, Beijing 100081, China. cheng_jinbo@126.com zqyuan@bmi.ac.cn zyuan620@yahoo.com.
Abstract:
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.
Insights
Calcium homeostasis modulator family protein 2 (Calhm2) drives Alzheimer's disease pathology by promoting microglial inflammation. Inhibiting Calhm2 in mice reduced neuroinflammation and cognitive decline, suggesting it as a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) is a leading neurodegenerative disorder characterized by neuronal calcium imbalance and microglial neuroinflammation.
- The precise role of calcium dysfunction in microglial activation and AD progression in vivo remains unclear.
- Calcium homeostasis modulator family protein 2 (Calhm2) expression is elevated in AD models.
Purpose of the Study:
- To investigate the role of Calhm2 in microglial activation and its contribution to Alzheimer's disease pathology.
- To determine if targeting Calhm2 can ameliorate AD-related neuroinflammation and cognitive deficits.
Main Methods:
- Utilized 5×FAD transgenic mice, a model for familial Alzheimer's disease.
- Generated conventional and microglial-specific Calhm2 knockout mouse models.
- Assessed amyloid-beta deposition, neuroinflammation markers, microglial activity (pro-inflammatory and phagocytic), and cognitive function.
- Evaluated the impact of Calhm2 knockout on lipopolysaccharide (LPS)-induced neuroinflammation.
Main Results:
- Conventional and microglial knockout of Calhm2 significantly reduced amyloid-beta deposition, neuroinflammation, and cognitive impairments in 5×FAD mice.
- Calhm2 knockout suppressed microglial pro-inflammatory responses while enhancing phagocytic capacity, restoring a balance between inflammation and phagocytosis.
- Calhm2 deficiency attenuated acute LPS-induced neuroinflammation.
Conclusions:
- Calhm2 plays a critical role in regulating microglial activation and promoting Alzheimer's disease pathology.
- Targeting Calhm2 presents a promising therapeutic strategy for Alzheimer's disease and other microglia-mediated neuroinflammatory conditions.
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