Taurine amino acid nih pvcs8/15/2023 ![]() ![]() One prominent hypothesis is that this increase in AD risk is due to the capability of apoE4 to increase the aggregation and decrease the clearance of Aβ 7, 8, 9, 10, 11, 12, 13. While a number of mechanisms have been proposed to help explain this APOE4-associated susceptibility to AD, the precise cause remains a source of debate. Although the APOE2, APOE3 and APOE4 alleles are normally present at a relative frequency of about 8%, 78% and 14%, respectively, the APOE4 allele is present at a relative frequency of about 37% in AD patients 5, with individuals who possess one or two APOE4 alleles having an odds ratio for AD of about 3 or 12, respectively 5, 6. Importantly, these isoform differences also have a major impact on the pathogenesis of late-onset AD. 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. 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, 2, 3. Possession of the ε4 allele of apolipoprotein E ( APOE) is the major genetic risk factor for late-onset Alzheimer’s disease (AD). 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. 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. APOE3 mice, but not in the EC of these mice. Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of APOE4 vs. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. In order to gain a more comprehensive understanding of APOE4′s role in AD pathogenesis, we performed a transcriptomics analysis of APOE4 vs. 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. However, the reason for the association between APOE4 and AD remains unclear. The ε4 allele of apolipoprotein E ( APOE) is the dominant genetic risk factor for late-onset Alzheimer’s disease (AD). ![]()
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