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d ert ity o ed S Accepted 2 June 2010 Available online xxxx Keywords: Mitochondria Bioenergetics Reproductive senescence Alzheimer's disease Estrogen ously demonstrated that mitochondrial bioenergetic deficits precede Alzheimer's Biochimica et Biophysica Acta xxx (2010) xxx–xxx BBAGEN-26896; No. of pages: 6; 4C: Contents lists available at ScienceDirect Biochimica et Bi j ourna l homepage: www.e ls The essential role of mitochondria in cellular bioenergetics and survival has been well established [1–3]. Further, mitochondrial dysfunction has been suggested to play a pivotal role in neurodegen- erative disorders, including Alzheimer's disease (AD) [1,4,5]. It has been shown that brain metabolism is declined in AD patients at least a decade before disease diagnosis [1,6–9]. Dysfunction in glucose metabolism, bioenergetics and mitochondrial function are consistent antecedents to development of Alzheimer pathology [10–18]. Re- cently we demonstrated that mitochondrial bioenergetic deficits precede Alzheimer's pathology in the female triple transgenic mouse bioenergetics in AD pathogenesis and disease progression. Basic science analyses indicate that the endogenous estrogen, 17β- estradiol (E2), significantly increased glucose uptake, glucose metab- olism, insulin growth factor signaling and the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism) [1,6,19]. The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of AD [1,6]. The ability of estrogen to sustain glucose as the primary fuel source in brain by Abbreviations: AD, Alzheimer's disease; 3xTgAD, disease; nonTg, non-transgenic; E2, 17β-estradiol; PDH, cytochrome c oxidase ⁎ Corresponding author. Pharmacology & Pharmace Southern California, Pharmaceutical Sciences Center, 19 Angeles, CA 90089, United States. Tel.: +323 442 1428; E-mail address: [email protected] (R.D. Brinton). 0304-4165/$ – see front matter © 2010 Elsevier B.V. Al doi:10.1016/j.bbagen.2010.06.002 Please cite this article as: J. Yao, et al., Dec senescence, Biochim. Biophys. Acta (2010) model of Alzheimer's disease (3xTgAD) [7]. These antecedent declines in brain metabolism indicate a potential causal role of mitochondrial 1. Introduction decline in both the nonTg and 3xTgAD brain which was indicative of alternative fuel generation with concomitant decline in ATP generation. Conclusions: These data indicate that reproductive senescence in the normal nonTg female brain parallels the shift to ketogenic/fatty acid substrate phenotype with concomitant decline in mitochondrial function and exacerbation of bioenergetic deficits in the 3xTgAD brain. General significance: These findings provide a plausible mechanism for increased life-time risk of AD in postmenopausal women and suggest an optimal window of opportunity to prevent or delay decline in bioenergetics during reproductive senescence. © 2010 Elsevier B.V. All rights reserved. determine the impact of reproductive senescence on mitochondrial function in the normal non-transgenic (nonTg) and 3xTgAD female mouse model of AD. Methods: Both nonTg and 3xTgAD female mice at 3, 6, 9, and 12 months of age were sacrificed and mitochondrial bioenergetic profile as well as oxidative stress markers were analyzed. Results: In both nonTg and 3xTgAD mice, reproductive senescence paralleled a significant decline in PDH, and Complex IV cytochrome c oxidase activity and mitochondrial ...

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