PMID- 32152337 OWN - NLM STAT- MEDLINE DCOM- 20201123 LR - 20221012 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 10 IP - 1 DP - 2020 Mar 9 TI - APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice. PG - 4277 LID - 10.1038/s41598-020-61142-8 [doi] LID - 4277 AB - The epsilon4 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 Abeta, 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. FAU - Area-Gomez, Estela AU - Area-Gomez E AD - Department of Neurology, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. AD - Institute of Human Nutrition, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. FAU - Larrea, Delfina AU - Larrea D AD - Department of Neurology, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. FAU - Pera, Marta AU - Pera M AD - Department of Neurology, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. AD - Department of Basic Sciences, Facultat de Medicina i Ciencies de la Salut, Universitat Internacional de Catalunya (UIC), 08195, Sant Cugat del Valles, Spain. FAU - Agrawal, Rishi R AU - Agrawal RR AD - Institute of Human Nutrition, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. FAU - Guilfoyle, David N AU - Guilfoyle DN AD - Center for Biomedical Imaging and Neuromodulation, Nathan S. Kline Institute, Orangeburg, NY, 10962, USA. FAU - Pirhaji, Leila AU - Pirhaji L AD - Department of Biological Engineering, Massachusetts Institute of Technology, 350 Brookline Street, Cambridge, MA, 02139, USA. FAU - Shannon, Kathleen AU - Shannon K AD - Animal Facility, Nathan S. Kline Institute, Orangeburg, NY, 10962, USA. FAU - Arain, Hirra A AU - Arain HA AD - Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. AD - Department of Pathology and Cell Biology, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. FAU - Ashok, Archana AU - Ashok A AD - Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. AD - Department of Pathology and Cell Biology, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. FAU - Chen, Qiuying AU - Chen Q AD - Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. FAU - Dillman, Allissa A AU - Dillman AA AD - Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, 20892, USA. FAU - Figueroa, Helen Y AU - Figueroa HY AD - Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. AD - Department of Pathology and Cell Biology, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. FAU - Cookson, Mark R AU - Cookson MR AUID- ORCID: 0000-0002-1058-3831 AD - Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, 20892, USA. FAU - Gross, Steven S AU - Gross SS AD - Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. FAU - Fraenkel, Ernest AU - Fraenkel E AUID- ORCID: 0000-0001-9249-8181 AD - Department of Biological Engineering, Massachusetts Institute of Technology, 350 Brookline Street, Cambridge, MA, 02139, USA. AD - Broad Institute, 415 Main Street, Cambridge, MA 02142, Cambridge, Massachusetts, 02139, USA. FAU - Duff, Karen E AU - Duff KE AD - Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. AD - Department of Pathology and Cell Biology, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. AD - UK Dementia Research Institute, University College London, Cruciform Building, Gower Street, London, WC1E 6BT, UK. FAU - Nuriel, Tal AU - Nuriel T AUID- ORCID: 0000-0002-5252-8048 AD - Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. tn2283@cumc.columbia.edu. AD - Department of Pathology and Cell Biology, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. tn2283@cumc.columbia.edu. LA - eng GR - R01 AG056387/AG/NIA NIH HHS/United States GR - K01 AG061264/AG/NIA NIH HHS/United States GR - T32 DK007647/DK/NIDDK NIH HHS/United States GR - F32 AG047797/AG/NIA NIH HHS/United States GR - K01AG061264/U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/International GR - R01 AG070202/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20200309 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Apolipoprotein E4) SB - IM MH - Animals MH - Apolipoprotein E4/*genetics MH - Brain/*metabolism MH - Energy Metabolism/*genetics MH - Male MH - *Metabolome MH - Mice MH - Mitochondria/genetics/metabolism/*pathology MH - *Transcriptome PMC - PMC7062695 COIS- K.E.D is on the board of directors of Ceracuity LLC. The authors declare no competing interests. EDAT- 2020/03/11 06:00 MHDA- 2020/11/24 06:00 PMCR- 2020/03/09 CRDT- 2020/03/11 06:00 PHST- 2019/03/22 00:00 [received] PHST- 2020/02/14 00:00 [accepted] PHST- 2020/03/11 06:00 [entrez] PHST- 2020/03/11 06:00 [pubmed] PHST- 2020/11/24 06:00 [medline] PHST- 2020/03/09 00:00 [pmc-release] AID - 10.1038/s41598-020-61142-8 [pii] AID - 61142 [pii] AID - 10.1038/s41598-020-61142-8 [doi] PST - epublish SO - Sci Rep. 2020 Mar 9;10(1):4277. doi: 10.1038/s41598-020-61142-8.