APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
09 03 2020
09 03 2020
Historique:
received:
22
03
2019
accepted:
14
02
2020
entrez:
11
3
2020
pubmed:
11
3
2020
medline:
24
11
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32152337
doi: 10.1038/s41598-020-61142-8
pii: 10.1038/s41598-020-61142-8
pmc: PMC7062695
doi:
Substances chimiques
Apolipoprotein E4
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4277Subventions
Organisme : NIA NIH HHS
ID : R01 AG056387
Pays : United States
Organisme : NIA NIH HHS
ID : K01 AG061264
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007647
Pays : United States
Organisme : NIA NIH HHS
ID : F32 AG047797
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : K01AG061264
Pays : International
Organisme : NIA NIH HHS
ID : R01 AG070202
Pays : United States
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