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Biological sex and DNA repair deficiency drive Alzheimer’s disease via systemic metabolic remodeling and brain mitochondrial dysfunction

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Abstract

Alzheimer’s disease (AD) is an incurable neurodegenerative disease that is more prevalent in women. The increased risk of AD in women is not well understood. It is well established that there are sex differences in metabolism and that metabolic alterations are an early component of AD. We utilized a cross-species approach to evaluate conserved metabolic alterations in the serum and brain of human AD subjects, two AD mouse models, a human cell line, and two Caenorhabditis elegans AD strains. We found a mitochondrial complex I-specific impairment in cortical synaptic brain mitochondria in female, but not male, AD mice. In the hippocampus, Polβ haploinsufficiency caused synaptic complex I impairment in male and female mice, demonstrating the critical role of DNA repair in mitochondrial function. In non-synaptic, glial-enriched, mitochondria from the cortex and hippocampus, complex II-dependent respiration increased in female, but not male, AD mice. These results suggested a glial upregulation of fatty acid metabolism to compensate for neuronal glucose hypometabolism in AD. Using an unbiased metabolomics approach, we consistently observed evidence of systemic and brain metabolic remodeling with a shift from glucose to lipid metabolism in humans with AD, and in AD mice. We determined that this metabolic shift is necessary for cellular and organismal survival in C. elegans, and human cell culture AD models. We observed sex-specific, systemic, and brain metabolic alterations in humans with AD, and that these metabolite changes significantly correlate with amyloid and tau pathology. Among the most significant metabolite changes was the accumulation of glucose-6-phosphate in AD, an inhibitor of hexokinase and rate-limiting metabolite for the pentose phosphate pathway (PPP). Overall, we identified novel mechanisms of glycolysis inhibition, PPP, and tricarboxylic acid cycle impairment, and a neuroprotective augmentation of lipid metabolism in AD. These findings support a sex-targeted metabolism-modifying strategy to prevent and treat AD.

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institutes on Aging, National Institutes of Health. The authors are grateful to the Baltimore Longitudinal Study of Aging study participants and staff for their dedication to these studies. We would like to thank Kelly Palagia (West coast metabolomics center, UC Davis) for performing the GC-TOF plasma metabolomics and Drs. Jong-Hyuk Lee and Anthony Moore for their critical review of the manuscript.

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Authors and Affiliations

  1. Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA

    Tyler G. Demarest, Darlene Estrada, Mansi Babbar, Sambuddha Basu, Deborah L. Croteau & Vilhelm A. Bohr

  2. Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA

    Tyler G. Demarest & Mark P. Mattson

  3. Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

    Vijay R. Varma, Uma V. Mahajan & Madhav Thambisetty

  4. Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA

    Ruin Moaddel

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Demarest, T.G., Varma, V.R., Estrada, D. et al. Biological sex and DNA repair deficiency drive Alzheimer’s disease via systemic metabolic remodeling and brain mitochondrial dysfunction. Acta Neuropathol 140, 25–47 (2020). https://doi.org/10.1007/s00401-020-02152-8

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  • DOI: https://doi.org/10.1007/s00401-020-02152-8

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