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Conditional knockout of AIM2 in microglia ameliorates synaptic plasticity and spatial memory deficits in a mouse
Lei Ye1, Mengsha Hu1,2, Rui Mao1
1Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Aims:
Synaptic dysfunction is a hallmark pathology of Alzheimer's disease (AD) and is strongly associated with cognitive impairment. Abnormal phagocytosis by the microglia is one of the main causes of synapse loss in AD. Previous studies have shown that the absence of melanoma 2 (AIM2) inflammasome activity is increased in the hippocampus of APP/PS1 mice, but the role of AIM2 in AD remains unclear.
Methods:
Injection of Aβ1-42 into the bilateral hippocampal CA1 was used to mimic an AD mouse model (AD mice). C57BL/6 mice injected with AIM2 overexpression lentivirus and conditional knockout of microglial AIM2 mice were used to confirm the function of AIM2 in AD. Cognitive functions were assessed with novel object recognition and Morris water maze tests. The protein and mRNA expression levels were evaluated by western blotting, immunofluorescence staining, and qRT-PCR. Synaptic structure and function were detected by Golgi staining and electrophysiology.
Results:
The expression level of AIM2 was increased in AD mice, and overexpression of AIM2 induced synaptic and cognitive impairments in C57BL/6 mice, similar to AD mice. Elevated expression levels of AIM2 occurred in microglia in AD mice. Conditional knockout of microglial AIM2 rescued cognitive and synaptic dysfunction in AD mice. Excessive microglial phagocytosis activity of synapses was decreased after knockout of microglial AIM2, which was associated with inhibiting complement activation.
Conclusion:
Our results demonstrated that microglial AIM2 plays a critical role in regulating synaptic plasticity and memory deficits associated with AD, providing a new direction for developing novel preventative and therapeutic interventions for this disease.
Insights
Microglial AIM2 inflammasome contributes to Alzheimer's disease (AD) by increasing synaptic loss and cognitive decline. Inhibiting microglial AIM2 in AD mice rescued synaptic function and memory deficits.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Synaptic dysfunction and cognitive impairment are key features of Alzheimer's disease (AD).
- Microglial abnormal phagocytosis contributes to synapse loss in AD.
- The role of the AIM2 inflammasome in AD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of the absent in melanoma 2 (AIM2) inflammasome in microglia in the context of Alzheimer's disease.
- To determine if AIM2 contributes to synaptic dysfunction and cognitive deficits in AD models.
Main Methods:
- An AD mouse model was created by injecting Aβ1-42 into the hippocampus.
- AIM2 overexpression and microglial-specific knockout mouse models were utilized.
- Cognitive function, synaptic integrity, and molecular changes were assessed using behavioral tests, Golgi staining, electrophysiology, western blotting, immunofluorescence, and qRT-PCR.
Main Results:
- AIM2 expression was elevated in AD mice, particularly in microglia, and its overexpression mimicked AD-related synaptic and cognitive impairments.
- Conditional knockout of microglial AIM2 ameliorated cognitive deficits and synaptic dysfunction in AD mice.
- Reduced microglial phagocytosis and complement activation were observed after microglial AIM2 knockout.
Conclusions:
- Microglial AIM2 plays a critical role in AD-associated synaptic plasticity and memory deficits.
- Targeting microglial AIM2 presents a potential therapeutic strategy for Alzheimer's disease.
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