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Cited by 23Alzheimer's disease research and treatmentsATP Synthase and ATPases ResearchNeuroscience and Neuropharmacology Research

Human ApoE ɛ2 Promotes Regulatory Mechanisms of Bioenergetic and Synaptic Function in Female Brain: A Focus on V-type H+-ATPase

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Woody, Sarah K., Zhou, Helen, Ibrahimi, Shaher, Dong, Yafeng, Zhao, Liqin·2016·Journal of Alzheimer's Disease
DOI 10.3233/jad-160307PMC PMC5849070
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Abstract

Humans possess three major isoforms of the apolipoprotein E (ApoE) gene encoded by three alleles: ApoE ɛ2 (ApoE2), ApoE ɛ3 (ApoE3), and ApoE ɛ4 (ApoE4). It is established that the three ApoE isoforms confer differential susceptibility to Alzheimer's disease (AD); however, an in-depth molecular understanding of the underlying mechanisms is currently unavailable. In this study, we examined the cortical proteome differences among the three ApoE isoforms using 6-month-old female, human ApoE2, ApoE3, and ApoE4 gene-targeted replacement mice and two-dimensional proteomic analyses. The results reveal that the three ApoE brains differ primarily in two areas: cellular bioenergetics and synaptic transmission. Of particular significance, we show for the first time that the three ApoE brains differentially express a key component of the catalytic domain of the V-type H+-ATPase (Atp6v), a proton pump that mediates the concentration of neurotransmitters into synaptic vesicles and thus is crucial in synaptic transmission. Specifically, our data demonstrate that ApoE2 brain exhibits significantly higher levels of the B subunit of Atp6v (Atp6v1B2) when compared to both ApoE3 and ApoE4 brains, with ApoE4 brain exhibiting the lowest expression. Our additional analyses show that Atp6v1B2 is significantly impacted by aging and AD pathology and the data suggest that Atp6v1B2 deficiency could be involved in the progressive loss of synaptic integrity during early development of AD. Collectively, our findings indicate that human ApoE isoforms differentially modulate regulatory mechanisms of bioenergetic and synaptic function in female brain. A more efficient and robust status in both areas-in which Atp6v may play a role-could serve as a potential mechanism contributing to the neuroprotective and cognition-favoring properties associated with the ApoE2 genotype.

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Cited by

Sorted by citations

Authors
Woody, S. K., Zhou, H., Ibrahimi, S., Dong, Y., & Zhao, L.
Affiliations
University of Kansas (US)
Corresponding author
Zhao, Liqin
ORCID
Zhou, Helen
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2016-08-03
Volume
53
Issue
3
Pages
1015-1031
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-160307
PMC
PMC5849070
OpenAlex
W2472493001
Cited by
23
References
8
Citations by year
2026: 4 · 2025: 3 · 2023: 4 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 3
FWCI
1.37
Type
journal article
Language
en
Open access
Locations
  • Journal of Alzheimer s Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • KU ScholarWorks (University of Kansas) (submittedVersion)
Funders
  • National Institute on Aging (P30AG035982)
  • National Institute of General Medical Sciences (P20GM103418)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
apolipoprotein E, APOE2
MeSH terms
Age Factors, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Energy Metabolism, Female, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Promoter Regions, Genetic, Synapses, Gene Expression Regulation, Enzymologic, Vacuolar Proton-Translocating ATPases, Mice, Apolipoprotein E4, Apolipoprotein E2, Plaque, Amyloid, Amyloidogenic Proteins

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