Abstract Details

The Search Tag Analyze Resource for GEO (STARGEO) platform allows for meta-analysis of genomic signatures of disease and tissue. STARGEO was implemented to search The National Center for Biotechnology Information Gene Expression Omnibus (GEO), an open database with more than 2 million genomic samples. 21 samples were analyzed: 7 neurologically healthy controls and 14 AD patients, including 7 EOAD patients and 7 FAD patients genetically determined by a PSEN1 gene mutation. The meta-data was then analyzed using Ingenuity Pathway Analysis.

Based on meta-analysis results, top upstream regulators were CAMP Responsive Element Binding Protein 1 (CREB1), beta-estradiol, and Synuclein Alpha (SNCA). Additionally, neuroinflammation, GABA, and Opioid signaling were identified as the top canonical pathways. Analysis further revealed significant upregulation of the genes TSNAX, BBIP1, and CMC4. 

Overactivation of the gene regulator CREB, also exhibited in FAD mouse brains with mutant presenilin, reveals that the resultant alteration of gene expression in brains of early-onset AD patients could play a role in the disease’s pathogenesis. In mice, overactivation of CREB resulted in a constitutive CaMK pathway, contributing to increased apoptosis and sensitization of cells to Aβ-induced death. The significance of the opioid signaling pathway also suggests that it may contribute to the pathogenesis of AD. Its dysfunction is linked to the degeneration of cholinergic neurons and potentially hyperphosphorylation of tau and neuroinflammation. The top upregulated genes discussed require further investigation to determine if they may be contributing factors to early-onset AD pathogenesis.