Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

Xin Ding, Jin Wang, Miaoxin Huang, Zhangpeng Chen, Jing Liu, Qipeng Zhang, Chenyu Zhang, Yang Xiang, Ke Zen () and Liang Li ()
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Xin Ding: Nanjing University
Jin Wang: Nanjing University
Miaoxin Huang: Nanjing University
Zhangpeng Chen: Nanjing University
Jing Liu: Nanjing University
Qipeng Zhang: Nanjing University
Chenyu Zhang: Nanjing University
Yang Xiang: Nanjing University
Ke Zen: Nanjing University
Liang Li: Nanjing University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Microglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

Date: 2021
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DOI: 10.1038/s41467-021-22301-1

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