Analysis of genes in human entorhinal cortext samples by age (selected from a pre-clinical study of experimental menopause in 3xTg-AD mice)

We produced new transcriptomic profiles of dementia-free human entorhinal cortex (n=99) and remodeled entorhinal cortex profiles from patients (n=64; Braak scores 0-6). There is a compelling link between menopause and Alzheimer's disease (AD), with few established molecular mechanisms. A lack of experimental models limits validation of causal drivers of these interactions. Here, we characterize the accelerated ovarian failure (OF) model of menopause in the triple-transgenic AD (3xTg-AD) mouse. Ovotoxin, 4-vinylcyclohexene diepoxide accelerated follicular loss, ablating circulating progesterone. OF resulted in decreased performance in the Y-maze, Novel Object Recognition, and Barnes Maze, consistent with accelerated AD. OF aggravated age-related impaired glucose tolerance and caused insulin resistance and these alterations correlated with the degree of cognitive impairment. Transcriptomic analyses of the mouse hippocampus identified 19 differentially regulated genes in OF mice, including some linked to AD, including C4b, Ifit3b, Cxcl13 and Gabrg2. Analyses of our 19 OF genes, identified that C4B expression was upregulated with both age and Braak score, while several revealed novel co-expression relationships, including between Shootin (SHTN1) and GABA receptor subunit (GABRG2). In summary, accelerated ovarian failure presents key cognitive, metabolic and molecular changes associated with age-related decline in cognitive function, indicating that it can be useful for the identification of novel therapeutic targets Nineteen genes were identified in an analysis of female triple-transgenic AD (3xTg-AD)(26) mice treated with Ovotoxin vinylcyclohexene dioxide (VCD; Sigma, cat. #94956) to induce menopause. Two hundred and twenty Human samples from NIH funded brain banks (see metadata) were shipped to University of Miami and RNA extracted (TRIZOL), and processed on Affymetrix Clariom D arrays. 190 samples passed QC, with a subbatch of samples from Icahn School of medicine being reject for having the wrong molecular sex (XIST expression). From these a subset of 99 were recorded to be free of evidence of dementia (histopathology). The CEL files from these 99 donors were processed using a custom CDF (provided), the data was adjusted using updated COMBAT, for biobank location and our candidate genes were subsetted and analysed with respect to donor age.