Ota_2025_Cells_14_

Ageing is a major risk factor for cognitive and physical decline, but its mechanisms remain poorly understood. This study aimed to detect early cognitive and physical changes, and to analyze the pathway involved by monitoring two groups of mice: a young and an adult group. The study has identified the types of molecules involved in the hippocampus. Adult mice (47 weeks) showed significantly reduced exploratory behavior compared to young mice (11 weeks), although spatial working memory showed no difference. In terms of physical function, grip strength was significantly reduced in adult mice. The Frailty Index (FI) further highlighted age-related changes in adult mice. To investigate the causes of cognitive decline, adult mice were categorized based on their declining cognitive function. Microarray analysis of their hippocampi revealed that the cholinergic receptor nicotinic alpha3 subunit (Chrna3) was significantly reduced in mice with cognitive decline compared to controls. Subsequent in vitro experiments showed that oxidative stress and cholinesterase inhibitors decreased Chrna3 expression, whereas nicotine and cytisine increased it. These results suggest that Chrna3 is a key factor in age-related cognitive decline. The development of therapeutic strategies targeting Chrna3 expression may offer promising avenues for preclinical and clinical research to mitigate cognitive ageing.