Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration
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Published on: February 5, 2018
Xin Ding1, Jin Wang1,2, Miaoxin Huang1
1Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, Chinese Academy of Medical Sciences Research Unit of Extracellular RNA, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
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.
Insights
Microglial SIRPα (Signal Regulatory Protein Alpha) protects synapses from excessive pruning. Loss of this receptor in Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are key regulators of synaptic remodeling in the central nervous system.
- Microglia-mediated synaptic pruning is influenced by the classical complement pathway.
- CD47 signaling, via its receptor SIRPα on microglia, is known to protect synapses during development.
Purpose of the Study:
- To elucidate the role of microglial SIRPα in synaptic pruning during neurodegenerative disease.
- To investigate the impact of microglial SIRPα modulation on Alzheimer's disease pathogenesis.
Main Methods:
- Utilized conditional knock-out mice with microglia-specific deletion of SIRPα.
- Examined synaptic density and microglial engulfment in mouse models.
- Analyzed microglial SIRPα expression in human Alzheimer's disease brain tissue.
Main Results:
- Microglia-specific deletion of SIRPα led to reduced synaptic density.
- Microglial SIRPα expression decreased with Alzheimer's disease progression in human samples.
- Loss of microglial SIRPα exacerbated synaptic loss and cognitive deficits in Alzheimer's disease mouse models.
Conclusions:
- Microglial SIRPα plays a crucial role in regulating synaptic pruning in the context of neurodegeneration.
- Reduced microglial SIRPα expression contributes to synaptic loss and cognitive impairment in Alzheimer's disease.
