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Ovariectomy Induces a Shift in Fuel Availability and Metabolism in the Hippocampus of the Female Transgenic Model of Familial Alzheimer's

PLoS ONE, ISSN: 1932-6203, Vol: 8, Issue: 3, Page: e59825
2013
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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-[F]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. © 2013 Ding et al.

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http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84875423210&origin=inward; http://dx.doi.org/10.1371/journal.pone.0059825; http://www.ncbi.nlm.nih.gov/pubmed/23555795; https://dx.plos.org/10.1371/journal.pone.0059825.g007; http://dx.doi.org/10.1371/journal.pone.0059825.g007; https://dx.plos.org/10.1371/journal.pone.0059825.g003; http://dx.doi.org/10.1371/journal.pone.0059825.g003; https://dx.plos.org/10.1371/journal.pone.0059825.g008; http://dx.doi.org/10.1371/journal.pone.0059825.g008; https://dx.plos.org/10.1371/journal.pone.0059825.g004; http://dx.doi.org/10.1371/journal.pone.0059825.g004; https://dx.plos.org/10.1371/journal.pone.0059825.g002; http://dx.doi.org/10.1371/journal.pone.0059825.g002; https://dx.plos.org/10.1371/journal.pone.0059825; https://dx.plos.org/10.1371/journal.pone.0059825.g001; http://dx.doi.org/10.1371/journal.pone.0059825.g001; https://dx.plos.org/10.1371/journal.pone.0059825.g006; http://dx.doi.org/10.1371/journal.pone.0059825.g006; https://dx.plos.org/10.1371/journal.pone.0059825.g009; http://dx.doi.org/10.1371/journal.pone.0059825.g009; https://dx.plos.org/10.1371/journal.pone.0059825.g005; http://dx.doi.org/10.1371/journal.pone.0059825.g005; https://dx.doi.org/10.1371/journal.pone.0059825.g003; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0059825.g003; https://dx.doi.org/10.1371/journal.pone.0059825.g002; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0059825.g002; https://dx.doi.org/10.1371/journal.pone.0059825.g005; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0059825.g005; https://dx.doi.org/10.1371/journal.pone.0059825.g006; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0059825.g006; https://dx.doi.org/10.1371/journal.pone.0059825.g008; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0059825.g008; https://dx.doi.org/10.1371/journal.pone.0059825.g001; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0059825.g001; https://dx.doi.org/10.1371/journal.pone.0059825.g004; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0059825.g004; https://dx.doi.org/10.1371/journal.pone.0059825.g007; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0059825.g007; https://dx.doi.org/10.1371/journal.pone.0059825; https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059825; https://dx.doi.org/10.1371/journal.pone.0059825.g009; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0059825.g009; http://dx.plos.org/10.1371/journal.pone.0059825.g004; http://dx.plos.org/10.1371/journal.pone.0059825; https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0059825&type=printable; http://www.plosone.org/article/metrics/info:doi/10.1371/journal.pone.0059825; http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0059825&type=printable; http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059825; http://dx.plos.org/10.1371/journal.pone.0059825.g005; http://dx.plos.org/10.1371/journal.pone.0059825.g003; http://dx.plos.org/10.1371/journal.pone.0059825.g006; http://dx.plos.org/10.1371/journal.pone.0059825.g001; http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0059825; http://dx.plos.org/10.1371/journal.pone.0059825.g007; http://dx.plos.org/10.1371/journal.pone.0059825.g008; http://dx.plos.org/10.1371/journal.pone.0059825.g002; http://dx.plos.org/10.1371/journal.pone.0059825.g009

Fan Ding; Jia Yao; Liqin Zhao; Zisu Mao; Shuhua Chen; Roberta Diaz Brinton; Consueb Borras

Public Library of Science (PLoS)

Multidisciplinary

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