APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

Abstract

the ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of Aβ, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of APOE4′s role in AD pathogenesis, we performed a transcriptomics analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original transcriptomics data, suggest that multiple bioenergetic pathways are differentially regulated by APOE4 expression in the EC of aged APOE mice in order to increase the mitochondrial coupling efficiency in this region. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, the observation that the EC is susceptible to differential bioenergetic regulation in response to a metabolic stressor such as APOE4 may point to a causative factor in the pathogenesis of AD. Possession of the ε4 allele of apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD). In normal physiology, the apoE protein plays a vital role in the transport of cholesterol and other lipids through the bloodstream, as well as within the brain 1-3. Although the three common isoforms of apoE (E2, E3 and E4) differ from each other at only two amino acids-apoE2 (Cys112, Cys158), apoE3 (Cys112, Arg158), apoE4 (Arg112, Arg158)-this small change in amino acid sequence has a large effect on the protein structure, resulting in differential affinities towards apoE's lipid cargo, as well as its receptors [see reviews by 1,4 ].

Identifying neuron subtype-specific metabolic network changes in single cell transcriptomics of Alzheimer’s Disease using perturb-Met

“…Phosphocreatine is a rapidly mobilizable reserve of high-energy phosphates that has previously been reported to be highly increased in the entorhinal cortex of APOE4 mice [30]. Our analysis further infers that microglia may contribute to increased phosphocreatine.…”

APOE interacts with tau PET to influence memory independently of amyloid PET in older adults without dementia

“…Notably, the interaction between tau PET and ε4 status was only significant within the memory domain. Several studies have noted increased atrophy, 47,48 tau PET uptake, 9 and bioenergetic changes 49 specifically within the MTL in the presence of the ε4 allele. Importantly, we examined the effect of Braak stage I/II (ie, MTL) tau on cognition given the importance of this region early in the AD pathologic continuum.…”

Hypothesis and Theory: Characterizing Abnormalities of Energy Metabolism Using a Cellular Platform as a Personalized Medicine Approach for Alzheimer’s Disease

“…Specifically, age-related and disease-specific mitochondrial damage leads to reduced efficiency of OxPhos, with neurons increasing OxPhos activity to compensate, which through altered redox reactions may abnormally upregulate glycolysis. This could be a consequence of numerous interacting factors, including mitochondrial dysfunction, in part through age-associated mitochondrial DNA deletions (Popadin et al, 2014;Taylor et al, 2014), and also through AD risk factors, such as Apoε4, which has been associated with altered cellular membrane composition and dysfunctional bioenergetics (Wu et al, 2018;Area-Gomez et al, 2020) by damaging the oxidative/mitochondrial system, in particular (Kharrazi et al, 2008;Maruszak et al, 2011;Chico et al, 2013). Mitochondrial oxidative stress is an early event in AD (Nunomura et al, 2001) and produces toxic ROS that damage DNA and other cell elements.…”