Abstract
Previously, we demonstrated that reproductive senescence in female triple transgenic Alzheimer's (3×TgAD) mice was paralleled by a shift towards a ketogenic profile with a concomitant decline in mitochondrial activity in brain, suggesting a potential association between ovarian hormone loss and alteration in the bioenergetic profile of the brain. In the present study, we investigated the impact of ovariectomy and 17β-estradiol replacement on brain energy substrate availability and metabolism in a mouse model of familial Alzheimer's (3×TgAD). Results of these analyses indicated that ovarian hormones deprivation by ovariectomy (OVX) induced a significant decrease in brain glucose uptake indicated by decline in 2-[18F]fluoro-2-deoxy-D-glucose uptake measured by microPET-imaging. Mechanistically, OVX induced a significant decline in blood-brain-barrier specific glucose transporter expression, hexokinase expression and activity. The decline in glucose availability was accompanied by a significant rise in glial LDH5 expression and LDH5/LDH1 ratio indicative of lactate generation and utilization. In parallel, a significant rise in ketone body concentration in serum occurred which was coupled to an increase in neuronal MCT2 expression and 3-oxoacid-CoA transferase (SCOT) required for conversion of ketone bodies to acetyl-CoA. In addition, OVX-induced decline in glucose metabolism was paralleled by a significant increase in Aβ oligomer levels. 17β-estradiol preserved brain glucose-driven metabolic capacity and partially prevented the OVX-induced shift in bioenergetic substrate as evidenced by glucose uptake, glucose transporter expression and gene expression associated with aerobic glycolysis. 17β-estradiol also partially prevented the OVX-induced increase in Aβ oligomer levels. Collectively, these data indicate that ovarian hormone loss in a preclinical model of Alzheimer's was paralleled by a shift towards the metabolic pathway required for metabolism of alternative fuels in brain with a concomitant decline in brain glucose transport and metabolism. These findings also indicate that estrogen plays a critical role in sustaining brain bioenergetic capacity through preservation of glucose metabolism.
Highlights
We demonstrated that a decline in mitochondrial bioenergetics precedes the development of AD pathology in the female triple transgenic Alzheimer’s (36TgAD) mouse model [1]
Following transition through reproductive senescence, enzymes required for long-chain fatty acid (HADHA) and ketone body (SCOT) metabolism were significantly increased whereas cytochrome c oxidase (Complex IV) collapsed by 40% in both the nonTg and 36TgAD brain which was predictive of a concomitant decline in ATP generation
We demonstrated that loss of ovarian hormones induced a decline in glucose-driven brain bioenergetics, which was associated with dysregulated body weight and temperature control
Summary
We demonstrated that a decline in mitochondrial bioenergetics precedes the development of AD pathology in the female triple transgenic Alzheimer’s (36TgAD) mouse model [1] In both normal and 36TgAD mice, reproductive senescence, both natural and ovariectomy-induced, resulted in a significant decline in aerobic glycolysis, PDH, and Complex IV cytochrome c oxidase activity, and mitochondrial respiration. Following transition through reproductive senescence, enzymes required for long-chain fatty acid (HADHA) and ketone body (SCOT) metabolism were significantly increased whereas cytochrome c oxidase (Complex IV) collapsed by 40% in both the nonTg and 36TgAD brain which was predictive of a concomitant decline in ATP generation These bioenergetic changes, observed during natural reproductive senescence, were recapitulated in an ovariectomy model of menopause [2]. Further in persons with AD, compromised brain glucose metabolism is accompanied by parallel activation of alternative metabolic pathways, as evidenced by a utilization ratio of 2:1 glucose to alternative substrate in persons with incipient AD compared to a ratio of 29:1 in healthy elderly controls [10]
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