SRA

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. Overall design: Fourteen old (range = 19.4 - 23.2 years) female rhesus macaques (Macaca mulatta) were socially housed indoors in pens (3–4 animals per pen). Daily meals at ~08:00 h and ~15:00 h were supplemented with fresh fruits or vegetables; fresh drinking water was available ad libitum. At Month 0, the animals' diet (Monkey Diet, LabDiet, Inc., St Louis, MO, USA) was replaced with unlimited access to a typical American diet or WSD (TAD Primate Diet; LabDiet, Inc.), which provided calories with 36% fat, 44% carbohydrates (includes 18.5% sugars) and 18% protein. In comparison, regular monkey chow provides calories with 13% fat, 69% complex carbohydrates (includes 6% sugars) and 18% protein. Approximately 6 weeks after the start of the WSD, all of the animals were OvH. Half of the females (n = 7, OvH-HT) were immediately started on hormone replacement therapy (HT) in the form of estradiol (E) E-containing elastomer capsules, which achieved serum E concentrations of 82.1 ± 0.9pg/ mL; the other half (n = 7) received empty capsules (placebo), which achieved serum E concentrations of 6.6 ± 0.2pg/mL on average 32 months. Serum E was measured every 2 months and the capsule replaced or its size adjusted as deemed appropriate [43]. Details on the average of serum E concentrations (high physiological) have been previously published, as well as the transient attenuation in body weight gain and improved insulin sensitivity by HT. After the 30-month duration of the study, a detailed necropsy protocol previously used in our laboratory was used to systematically collect brain tissues from all subjects.