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Published on: March 23, 2011
Neuronal CD47 induces behavioral alterations and ameliorates microglial synaptic pruning in wild-type and Alzheimer's
Wenjie Hu1,2,3,4, Mengting Chen5,2,3,4, Yuxue Lin5,2,3,4
1Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230022, China.
Background:
Microglia are brain-resident macrophages that play a crucial role in synapse pruning during the development and progression of various neuropsychiatric disorders, including autism spectrum disorder (ASD) and Alzheimer's disease (AD). Mechanistically, CD47 protein acts as a potent 'do not eat me' signal, protecting synapses from phagocytosis by microglia. However, the functional role of the upregulated neuronal CD47 signal under both physiological and pathological conditions remains unclear.
Results:
We utilized an adeno-associated virus gene expression system to induce neuron-specific overexpression of CD47 in wild-type and 5xFAD mice, assessing its effects on microglial synaptic phagocytosis and mouse behaviors. Our results indicate that neuronal CD47 induces ASD-like behaviors and synaptic pruning defects, while promoting behavioral disinhibition and improving memory in wild-type mice. Single-nucleus RNA sequencing was employed to profile gene expression patterns in subpopulations of neurons and microglia. Notably, neuronal CD47 enhances synaptic pathways in neurons and particularly shifts microglial subpopulations from a disease-associated state to a homeostatic state. Additionally, neuronal CD47 reduces excessive microglial synaptic phagocytosis induced by Aβ pathology in 5xFAD mice.
Conclusion:
Our study provides evidence that neuronal CD47 overexpression results in synaptic pruning defects and is involved in the pathogenesis of ASD, while also playing a beneficial role in mitigating excessive synaptic loss in Alzheimer's disease.
Insights
Neuronal CD47 overexpression causes autism spectrum disorder-like symptoms and synaptic defects. However, it also improves memory and reduces synaptic loss in Alzheimer's disease models.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia, brain immune cells, are key in synapse pruning for neuropsychiatric disorders like autism spectrum disorder (ASD) and Alzheimer's disease (AD).
- Neuronal CD47 acts as a 'do not eat me' signal, preventing microglial phagocytosis of synapses.
- The precise function of increased neuronal CD47 in health and disease is not fully understood.
Purpose of the Study:
- To investigate the impact of neuron-specific CD47 overexpression on microglial synaptic pruning and behavior in mice.
- To elucidate the molecular mechanisms underlying CD47's effects on neuronal and microglial function.
Main Methods:
- Adeno-associated virus system for neuron-specific CD47 overexpression in wild-type and 5xFAD mice.
- Behavioral assessments to evaluate ASD-like symptoms, disinhibition, and memory.
- Single-nucleus RNA sequencing to analyze gene expression in neurons and microglia.
Main Results:
- Neuronal CD47 overexpression induced ASD-like behaviors and synaptic pruning defects in wild-type mice.
- Enhanced synaptic pathways in neurons and shifted microglia towards a homeostatic state.
- Reduced excessive microglial synaptic phagocytosis in 5xFAD mice, mitigating Aβ pathology effects.
Conclusions:
- Neuronal CD47 overexpression is implicated in ASD pathogenesis through synaptic pruning defects.
- Neuronal CD47 plays a protective role in AD by reducing excessive synaptic loss.
