ABSTRACT: Obesity during menopause contributes risk for mood disorders, dementia and Alzheimer’s disease (AD). Given the high prevalence of obesity among postmenopausal women there is an urgent need to evaluate the efficacy of hormone therapy (HT) administered immediately (vs delayed) at menopause in different brain regions involved in memory and cognition. Here, and to more closely replicate the endocrine environment of obese postmenopausal women, either on or off HT, middle-aged female rhesus macaques were ovariectomized/hysterectomized (OvH) and maintained on a high-fat, high-sugar, obesogenic Western-style diet (WSD) for 30 months; half of the animals received HT immediately after OvH and half served as placebo controls. RNAseq of the occipital (OC) and prefrontal cortex (PFC), hippocampus (HIP) and amygdala (AMG), identified 293, 379, 505 and 4,993 differentially expressed genes (DEGs), respectively. Pathway enrichment analysis, identified an activation of neuroinflammation in OC and HIP, but an inhibition in the AMG with HT. Synaptogenesis, circadian rhythm, mitochondrial dysfunction, mTOR, glutamate, serotonin, GABA, dopamine, noradrenaline/adrenaline, glucocorticoid receptor signaling. neuronal NOS and amyloid processing were exclusively enriched in AMG. As compared to the placebo control group, most of these signaling pathways are downregulated after HT, suggesting a protective effect of HT in OvH females under a WSD. Overall, our results suggest that a chronic obesogenic diet may induce a wide range of alterations in multiple signaling pathways that are linked to age-associated brain pathology and dementia. In these individuals, HT seems to have a protective effect against neuroinflammation, amyloid beta depositions and tau tangles formation.
