基于转录组学测序探讨衰老驱动APP/PS1小鼠阿尔兹海默病进展的关键基因与通路OA

Objective To analyze the effects of ageing on AD at the molecular level through transcriptomic se-quencing.Methods This study used 4-month-old male WT and APP/PS 1 mice,as well as 18-month-old male WT and APP/PS 1 mice.Body weights were measured,and learning and memory as well as motor function were assessed using the Morris water maze,rotarod and endurance tests;total cortical RNA was extracted for RNA-seq library preparation and sequencing,and differentially expressed genes were identified via GO and KEGG pathway enrichment analyses,with key genes validated by RT-qPCR.Results Compared with 18-month-old WT mice and 4-month-old APP/PS 1 mice,18-month-old APP/PS 1 mice exhibited significantly reduced body weight,impaired motor endurance and balance/coordination,and marked decline in learning and memory function;volcano plots and clustering heatmaps indicated that the four comparison groups(APP/PS1-4 vs APP/PS1-18,WT-4 vs WT-18,WT-4 vs APP/PS1-4,WT-18 vs APP/PS1-18)and showed significant differences in clustering analysis and gene expression patterns based on age and genotype;Venn diagram results indicated that 58 core genes were associated with the synergistic overlap effect of ageing and AD,and these 58 differentially expressed genes were used for subsequent GO and KEGG enrichment analyses;GO and KEGG functional enrichment analyses indicated that the differentially expressed genes were specifically enriched in biological processes,cellular com-ponents,molecular functions,and signaling pathways closely associated with AD pathology;RT-qPCR was used to validate the key gene PDYN.Conclusion This study confirms that ageing exacerbates AD-related func-tional impairments and pathological phenotypes in APP/PS1 mice.It is associated with key genes involved in cognitive impairment and motor decline in ageing-induced AD mice,and the relevant enriched pathways collec-tively constitute a core molecular regulatory network driving the progression of AD through ageing.