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

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 functi

SUBMITTER: Demarest TG 

PROVIDER: S-EPMC7537767 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature