Absent in melanoma 2 mediates aging‐related cognitive dysfunction by acting on complement‐dependent microglial phagocytosis

• Published in: Aging cell Vol. 22; no. 7; pp. e13860 - n/a
• Main Authors: Ye, Lei, Shu, Shu, Jia, Junqiu, Sun, Min, Xu, Siyi, Bao, Xinyu, Bian, Huijie, Liu, Yi, Zhang, Meijuan, Zhu, Xiaolei, Bai, Feng, Xu, Yun
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2023; John Wiley and Sons Inc
• Subjects: Aging; Aging - metabolism; AIM2; Alzheimer's disease; Animals; Anxiety; Cognitive ability; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; complement; Dentate gyrus; Inflammasomes; Inflammasomes - metabolism; Melanoma; Melanoma - metabolism; Memory; Mice; microglia; Microglia - metabolism; Nervous system; pattern separation; Phagocytosis; Protein expression; Proteins; Structure-function relationships; synaptic loss; Synaptic plasticity; pattern separation; AIM2; aging; synaptic loss; complement; microglia
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.13860

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. Pattern separation (PS) dysfunction is a 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) region of the hippocampus. Increased expression of absent in melanoma 2 in the DG region regulates microglial activation in synaptic pruning via the complement pathway, thereby leading to impaired synaptic plasticity and PS behavior in aging mice.