title: Ovariectomy induces a shift in fuel availability and metabolism in the hippocampus of the female transgenic model of familial Alzheimer's.
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-[(18)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.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Fan
authors.initials: F
authors.lastname: Ding
authors.forename: Jia
authors.initials: J
authors.lastname: Yao
authors.forename: Liqin
authors.initials: L
authors.lastname: Zhao
authors.forename: Zisu
authors.initials: Z
authors.lastname: Mao
authors.forename: Shuhua
authors.initials: S
authors.lastname: Chen
authors.forename: Roberta Diaz
authors.initials: RD
authors.lastname: Brinton
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006624:Hippocampus / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D007773:Lactates / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010052:Ovariectomy; D010053:Ovary / Q000378:metabolism; D049268:Positron-Emission Tomography; D012881:Skin Temperature; D055114:X-Ray Microtomography
chemical_list: D016229:Amyloid beta-Peptides; D004967:Estrogens; D007527:Isoenzymes; D007773:Lactates; D004958:Estradiol; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; C409667:lactate dehydrogenase 1; D005947:Glucose
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