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 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 Vilhelm A.

Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease

“…Although Lpl was upregulated across all AD-associated clusters of the hippocampus ( Figures 4 A and 4B), it was visibly upregulated in the CA1-2 and CA3 sublayers of the hippocampus ( Figures 4 C and S8 ). We have previously demonstrated Lpl protein upregulation by western blotting and suggested that it may contribute to altered fat metabolism in our mice ( Demarest et al., 2020 ). Thy1 was also upregulated in the AD strains' CA1 regions and throughout the brain hemisphere.…”

Metabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease

“…The accumulation of G6P can reduce hexokinase activity by competitively inhibiting ATP binding to the active site of the enzyme (Liu et al, 1999). In addition, an unbiased metabolomics approach demonstrated G6P accumulation in humans and mice with AD, which restrains glycolysis (Demarest et al, 2020). Hexokinase binds to the OMM via the voltage-dependent anion channel (VDAC), which controls the mitochondrial permeability transition pore (MPTP) (Harris et al, 2014).…”

“…A decreased level of GLUT1 and GLUT3 Simpson et al, 1994; The downregulation of hexokinase triggered by the increased G6P competitively binding with hexokinase Decrease the concentration of G6P Increase the activity of hexokinase in order to facilitate glycolysis Liu et al, 1999;Demarest et al, 2020 The inhibition of neuroprotective effects of 2DG caused by an increased concentration of NADH Control the activity of GAPDH Decrease the concentration of NADH and promote 2DG to inhibit the effect of Aβ on neuronal cells Vilalta and Brown, 2014;Kim et al, 2017;Shen et al, 2017 A decreased level of acetyl-CoA Treat with acetyl-L-carnitine which provides additional acetyl-CoA…”

α-Lipoic Acid Maintains Brain Glucose Metabolism via BDNF/TrkB/HIF-1α Signaling Pathway in P301S Mice

“…DNA repair deficiency is believed to deteriorate the glucose metabolism by driving mitochondrial dysfunction (Demarest et al, 2020 ). Herein, we evaluated the expression levels of three important DNA repair enzymes, MTH1, OGG1/2, and MUTYH (Nakabeppu, 2014 ).…”

“…DNA repair deficiency contributes to mitochondrial dysfunction and deteriorates the glucose metabolism (Demarest et al, 2020 ). MutY homolog (MUTYH), MutT Homolog 1 (MTH1) and Oxoguanine DNA glycosylase 1 and 2 (OGG1/2) are crucial DNA repair enzymes, the oxidative DNA damage can be minimized by the functions of MUTYH with the mispaired bases, MTH1 with oxidized dNTPs and OGG1/2 with the 7,8-dihydro-8-oxoguanine (8oxoG).…”