TY - JOUR
T1 - Effects of estradiol supplementation on the brain transcriptome of old rhesus macaques maintained on an obesogenic diet
AU - Cervera-Juanes, Rita
AU - Darakjian, Priscila
AU - Ball, Megan
AU - Kohama, Steven
AU - Urbanski, Henryk F.
N1 - Funding Information:
This work was supported by National Institutes of Health grants AG-029612, AG-062220, OD-011092, and OD-011895.
Publisher Copyright:
© 2021, American Aging Association.
PY - 2022/2
Y1 - 2022/2
N2 - Obesity, the cessation of ovarian steroids with menopause, and age are risk factors for mood disorders, dementia, and Alzheimer’s disease (AD). However, immediate hormone therapy (HT) after menopause may have beneficial effects in different brain regions involved in memory and cognition. To more closely replicate the age, endocrine, and metabolic 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 4993 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, epinephrine/norepinephrine, 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 tangle formation.
AB - Obesity, the cessation of ovarian steroids with menopause, and age are risk factors for mood disorders, dementia, and Alzheimer’s disease (AD). However, immediate hormone therapy (HT) after menopause may have beneficial effects in different brain regions involved in memory and cognition. To more closely replicate the age, endocrine, and metabolic 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 4993 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, epinephrine/norepinephrine, 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 tangle formation.
KW - Alzheimer’s disease
KW - Brain
KW - Estradiol
KW - Rhesus macaque
KW - Western-style diet
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U2 - 10.1007/s11357-021-00453-8
DO - 10.1007/s11357-021-00453-8
M3 - Article
C2 - 34642852
AN - SCOPUS:85117045196
VL - 44
SP - 229
EP - 252
JO - GeroScience
JF - GeroScience
SN - 2509-2715
IS - 1
ER -