Abstract
We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3–15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6–9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential targets for preventing shifts to less efficient bioenergetic fuels and transition to the ketogenic phenotype of the Alzheimer's brain.
Highlights
We demonstrated that loss of ovarian hormones and reproductive senescence (9–12 months) during female aging were associated with a significant decline in aerobic glycolysis and mitochondrial oxidative phosphorylation as well as decreased activities of key bioenergetic enzymes, pyruvate dehydrogenase (PDH) and Complex IV cytochrome c oxidase (COX) [1,2,3,4]
Based on our earlier findings that the female aging brain developed deficits in aerobic glycolysis and mitochondrial respiration during reproductive senescence that were followed by increased expression of enzymes required for long-chain fatty acid (HADHA) and ketone body (SCOT) metabolism [2,4], we investigated the expression of substrate transporters during the reproductive senescence transition
Results of analyses reported indicated that 1) decline in brain glucose uptake occurred early in the process of female brain aging; 2) decline in brain glucose uptake is paralleled by decline in glucose transporter expression in neurons and rise in glial associated glucose transporters; 3) decline in brain glucose uptake and neuronal glucose transporter expression are paralleled by decline in key metabolic enzymes required for glucose metabolism; 4) decline in glucose metabolism is paralleled by increases in alternative substrate supply and associated transporters (MCT2 and MCT4); and lastly 5) these changes in brain glucose supply and the system required for glucose transport and metabolism precede development of mitochondrial dysfunction
Summary
We demonstrated that loss of ovarian hormones and reproductive senescence (9–12 months) during female aging were associated with a significant decline in aerobic glycolysis and mitochondrial oxidative phosphorylation as well as decreased activities of key bioenergetic enzymes, pyruvate dehydrogenase (PDH) and Complex IV cytochrome c oxidase (COX) [1,2,3,4]. The decline in PDH activity was accompanied by a significant increase in enzymes required for ketone body utilization (3-oxoacid-CoA transferase 1, SCOT) and long-chain fatty acid metabolism (hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), HADHA), which are indicative of compensatory fuel utilization [2]. These bioenergetic changes observed during reproductive senescence were recapitulated in the ovariectomized rodent model of human menopause [3]. Consistent with basic science findings, data emerging from clinical positron emission tomography with 2-[18F]fluoro-2-deoxyD-glucose (FDG-PET) analyses demonstrate a significant decline in cerebral glucose metabolic rate (CMRglu) in the posterior cingulate (PCC) in postmenopausal women [5] and a decline in cognition during the perimenopause transition in women [6,7]
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