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Absent in melanoma 2 mediates aging-related cognitive dysfunction by acting on complement-dependent microglial
Lei Ye1, Shu Shu1, Junqiu Jia1
1Department of Neurology, Nanjing Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Medical School, Nanjing University, Nanjing, China.
Abstract:
Pattern separation (PS) dysfunction is a type of cognitive impairment that presents early during the aging process, and this deficit has been attributed to structural and functional alterations in the dentate gyrus (DG) of the hippocampus. Absent in melanoma 2 (AIM2) is an essential component of the inflammasome. However, whether AIM2 plays a role in aging-associated cognitive dysfunction remains unclear. Here, we found that PS function was impaired in aging mice and was accompanied by marked synaptic loss and increased expression of AIM2 in the DG. Subsequently, we used an AIM2 overexpression virus and mice with AIM2 deletion to investigate the role of AIM2 in regulating PS function and synaptic plasticity and the mechanisms involved. Our study revealed that AIM2 regulates microglial activation during synaptic pruning in the DG region via the complement pathway, leading to impaired synaptic plasticity and PS function in aging mice. These results suggest a critical role for AIM2 in regulating synaptic plasticity and PS function and provide a new direction for ameliorating aging-associated cognitive dysfunction.
