Ovariectomy induces a shift in fuel availability and metabolism in the hippocampus of the female transgenic model of familial Alzheimer's.
Ovariectomy induces a shift in fuel availability and metabolism in the hippocampus of the female transgenic model of familial Alzheimer's.
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DOI：
10.1371/journal.pone.0059825
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Brinton RD
中科院分区：
文献类型：
--
作者：
Ding F;Yao J;Zhao L;Mao Z;Chen S;Brinton RD
此前，我们证明了雌性三重转基因阿尔茨海默病(3×TgAD)小鼠的生殖衰老与向生酮类型的转变平行，并伴随着脑中线粒体活性的下降，这表明卵巢激素丢失与大脑生物能量谱的改变之间存在潜在的关联。在本研究中，我们研究了卵巢切除和17β-雌二醇替代对家族性阿尔茨海默病(3×TgAD)小鼠脑能量底物可获得性和代谢的影响。这些分析的结果表明，卵巢切除(OVX)的卵巢激素剥夺导致脑葡萄糖摄取显着下降，这表现为MicroPET-成像测量的2-[18F]氟-2-脱氧-D-葡萄糖摄取的下降。机制上，OVX可显著降低血脑屏障特异性葡萄糖转运体的表达、己糖激酶的表达和活性。葡萄糖供应的下降伴随着胶质细胞LDH5表达和LDH5/LDH1比值的显著上升，这表明乳酸的产生和利用。同时，血清酮小体浓度显著升高，这与神经元MCT2表达和酮体转化为乙酰辅酶A所需的3-氧代酸-辅酶A转移酶(SCOT)的增加有关。此外，去卵巢引起的葡萄糖代谢下降与Aβ寡聚体水平显著增加是平行的。17-β-雌二醇保护了葡萄糖驱动的脑代谢能力，并部分阻止了去势引起的生物能底物的转移，表现为葡萄糖摄取、葡萄糖转运体表达和与有氧糖酵解相关的基因表达。17-β-雌二醇也可部分抑制去卵巢引起的A-β寡聚体水平的升高。总而言之，这些数据表明，在阿尔茨海默氏症的临床前模型中，卵巢激素的丢失与向大脑中替代燃料代谢所需的代谢途径的转变平行，并伴随着大脑葡萄糖运输和代谢的下降。这些发现还表明，雌激素通过保护葡萄糖代谢，在维持大脑的生物能量能力方面发挥着关键作用。
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.
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影响因子：
5.7
作者：
Chen, Kewei;Langbaum, Jessica B. S.;Fleisher, Adam S.;Ayutyanont, Napatkamon;Reschke, Cole;Lee, Wendy;Liu, Xiaofen;Bandy, Dan;Alexander, Gene E.;Thompson, Paul M.;Foster, Norman L.;Harvey, Danielle J.;de Leon, Mony J.;Koeppe, Robert A.;Jagust, William J.;Weiner, Michael W.;Reiman, Eric M.
通讯作者：
Reiman, Eric M.
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影响因子：
2.4
作者：
Laughton, Jocelyn D.;Bittar, Philippe;Charnay, Yves;Pellerin, Luc;Kovari, Eniko;Magistretti, Pierre J.;Bouras, Constantin
通讯作者：
Bouras, Constantin
影响因子：
15.9
作者：
Barros, LF;Porras, OH;Bittner, CX
通讯作者：
Bittner, CX
影响因子：
9.9
作者：
Eberling, JL;Reed, BR;Jagust, WJ
通讯作者：
Jagust, WJ
影响因子：
4.8
作者：
Gimenez-Cassina, Alfredo;Lim, Filip;Diaz-Nido, Javier
通讯作者：
Diaz-Nido, Javier