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

AbstractAlzheimer ’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 twoCaenorhabditis 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, Pol β 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 ma le, 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 metabol ism in humans with AD, and in AD mice. We determined that this metabolic shift is necessary for cellular and organismal survival inC. elegans, and human cell culture AD models. We observed sex-specific, systemic, and brain metabolic alter...
Source: Acta Neuropathologica - Category: Neurology Source Type: research