The incidence of Alzheimer's disease (AD) in postmenopausal women is significantly increased with ageing. Menopause induced ovarian estrogen deficiency has been regarded as one of the causative risk factor of AD, but currently the detail mechanisms underlying estrogen regulation on the hippocampus remain unclear. This study aimed to uncover the potential pathways and key molecules through which estrogen deficiency induced by ovariectomy promotes AD pathogenesis by integrating transcriptomic and proteomic analyses.

The ovariectomy (OVX) mouse model was established to simulate postmenopausal estrogen decline. Transcriptomic (n=3) and proteomic (n=3) differences in the hippocampal tissues of OVX mice were analyzed using RNA sequencing and protein mass spectrometry. Co-trend molecules identified from both omics datasets were subjected to GO/KEGG enrichment and cluster analyses. These molecules were further compared with the human AD hippocampal database (AlzDate) for expression trend consistency; and online resources such as String, GeneCards/Uniports were employed to analyze protein interactions and networks of the co-trend genes to identify key molecules.

A total of 139 differentially expressed genes (DEG) and 248 differentially expressed proteins (DEP) were identified, with 18 molecules showing consistent expression trends in both omics. Functional enrichment analysis revealed that these molecules were primarily involved in axonogenesis, cytoskeleton dynamics regulation, and long-chain fatty acid transport. After comparison with the human AD database, 11 of the 18 co-trend molecules exhibited expression inhibition consistent with AD-associated genes in the human hippocampal databases. Interaction network analysis identified Aldoc (involved in glycolysis), Aldh6a1 (involved in ROS scavenging), Etnppl (involved in mitochondrial energy metabolism), and Itih3 (involved in hyaluronic acid-mediated extracellular matrix remodeling) as key genes contributing to AD pathogenesis. Additionally, 3 co-trend molecules (Prxl2a, Set, Plin4) were not detected in human AD databases.

Postmenopausal estrogen deficiency decreases the expression levels of hippocampal Aldoc, Etnppl and Aldh6a1 then affects mitochondrial energy metabolism; and decreases levels of Itih3 expression then disables extracellular matrix remodeling. These effects collectively impair hippocampal axonal regenerative capacity, destabilize the cytoskeleton, and hinder the transport of long-chain fatty acids, ultimately driving the progression of AD pathology.