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BBAGEN 26896 No of pages 6 4C Biochimica et Biophysica Acta xxx 2010 xxx xxx Contents lists available at ScienceDirect Biochimica et Biophysica Acta j o u r n a l h o m e p a g e w w w e l s ev i e r c o m l o c a t e b b a g e n Decline in mitochondrial bioenergetics and shift to ketogenic pro le in brain during reproductive senescence Jia Yao a Ryan T Hamilton a Enrique Cadenas a Roberta Diaz Brinton a b a b Department of Pharmacology and Pharmaceutical Sciences School of Pharmacy University of Southern California Los Angeles CA 90033 United States Program in Neuroscience University of Southern California Los Angeles CA 90089 United States a r t i c l e i n f o Article history Received 28 April 2010 Received in revised form 30 May 2010 Accepted 2 June 2010 Available online xxxx Keywords Mitochondria Bioenergetics Reproductive senescence Alzheimer s disease Estrogen a b s t r a c t Background We have previously demonstrated that mitochondrial bioenergetic de cits precede Alzheimer s pathology in the female triple transgenic Alzheimer s 3xTgAD mouse model Herein we sought to 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 sacri ced and mitochondrial bioenergetic pro le as well as oxidative stress markers were analyzed Results In both nonTg and 3xTgAD mice reproductive senescence paralleled a signi cant decline in PDH and Complex IV cytochrome c oxidase activity and mitochondrial respiration During the reproductive senescence transition both nonTg and 3xTgAD mice exhibited greater individual variability in bioenergetic parameters suggestive of divergent bioenergetic phenotypes Following transition through reproductive senescence enzymes required for long chain fatty acid HADHA and ketone body SCOT metabolism were signi cantly increased and variability in cytochrome c oxidase Complex IV collapsed

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