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Cited by 102Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Human ApoE Isoforms Differentially Modulate Glucose and Amyloid Metabolic Pathways in Female Brain: Evidence of the Mechanism of Neuroprotection by ApoE2 and Implications for Alzheimer’s Disease Prevention and Early Intervention

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Keeney, Jeriel Thomas-Richard, Ibrahimi, Shaher, Zhao, Liqin·2015·Journal of Alzheimer's Disease
DOI 10.3233/jad-150348PMC PMC5485924
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Abstract

Three major genetic isoforms of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4, exist in humans and lead to differences in susceptibility to Alzheimer's disease (AD). This study investigated the impact of human ApoE isoforms on brain metabolic pathways involved in glucose utilization and amyloid-β (Aβ) degradation, two major areas that are significantly perturbed in preclinical AD. Hippocampal RNA samples from middle-aged female mice with targeted human ApoE2, ApoE3, and ApoE4 gene replacement were comparatively analyzed with a qRT-PCR custom array for the expression of 85 genes involved in insulin/insulin-like growth factor (Igf) signaling. Consistent with its protective role against AD, ApoE2 brain exhibited the most metabolically robust profile among the three ApoE genotypes. When compared to ApoE2 brain, both ApoE3 and ApoE4 brains exhibited markedly reduced levels of Igf1, insulin receptor substrates (Irs), and facilitated glucose transporter 4 (Glut4), indicating reduced glucose uptake. Additionally, ApoE4 brain exhibited significantly decreased Pparg and insulin-degrading enzyme (Ide), indicating further compromised glucose metabolism and Aβ dysregulation associated with ApoE4. Protein analysis showed significantly decreased Igf1, Irs, and Glut4 in ApoE3 brain, and Igf1, Irs, Glut4, Pparg, and Ide in ApoE4 brain compared to ApoE2 brain. These data provide the first documented evidence that human ApoE isoforms differentially affect brain insulin/Igf signaling and downstream glucose and amyloid metabolic pathways, illustrating a potential mechanism for their differential risk in AD. A therapeutic strategy that enhances brain insulin/Igf1 signaling activity to a more robust ApoE2-like phenotype favoring both energy production and amyloid homeostasis holds promise for AD prevention and early intervention.

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Authors
Keeney, J. T.-R., Ibrahimi, S., & Zhao, L.
Affiliations
University of Kansas (US)
Corresponding author
Zhao, Liqin
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2015-09-09
Volume
48
Issue
2
Pages
411-424
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-150348
PMC
PMC5485924
OpenAlex
W2261760577
Cited by
102
References
13
Citations by year
2026: 10 · 2025: 11 · 2024: 8 · 2023: 10 · 2022: 9 · 2021: 10 · 2020: 8 · 2019: 12 · 2018: 11 · 2017: 6 · 2016: 7
FWCI
5.34
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)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E isoforms, APOE2
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Female, Glucose, Humans, Insulin, Mice, Inbred C57BL, Mice, Transgenic, RNA, Sex Characteristics, Somatomedins, Gene Expression, Amyloid beta-Peptides, Glucose Transporter Type 4, Insulin Receptor Substrate Proteins

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