Conditional knockout of AIM2 in microglia ameliorates synaptic plasticity and spatial memory deficits in a mouse model of Alzheimer's disease.
CNS Neurosci Ther
; 30(6): e14555, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38105588
ABSTRACT
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 Aß1-42 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Microglia
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Camundongos Knockout
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Modelos Animais de Doenças
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Doença de Alzheimer
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Memória Espacial
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Transtornos da Memória
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Camundongos Endogâmicos C57BL
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Plasticidade Neuronal
Limite:
Animals
Idioma:
En
Revista:
CNS Neurosci Ther
Assunto da revista:
NEUROLOGIA
/
TERAPEUTICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China