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Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response

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Johnson, Lance A, Torres, Eileen Ruth, Weber Boutros, Sydney, Patel, Esha, Akinyeke, Tunde, Alkayed, Nabil J, Raber, Jacob·2019·Journal of Cerebral Blood Flow & Metabolism
DOI 10.1177/0271678x17746186PMC PMC6498752
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Abstract

Metabolic dysfunction, commonly a result of diets high in saturated fats and sugar, is associated with impaired cognitive function and an increased risk of age-related cognitive decline (ACD) and Alzheimer’s disease (AD). Compared to the E3 isoform of apolipoprotein (apoE), the E4 isoform is a major genetic risk factor for ACD, AD, and for developing cognitive impairments following various environmental challenges, including dietary challenges such as a high-fat diet (HFD). Both insulin resistance (IR) and E4 are associated with metabolic and vascular impairments. Deficits in cerebral metabolism and cerebrovascular function have been proposed as initiating events leading to these impairments. In the current study, we employed a model of human apoE targeted replacement mice and HFD-induced obesity to study the potential link between E4 and IR, at rest and following a postprandial challenge. HFD-induced IR was associated with impaired cognition, reduced cerebral blood volume and decreased glucose uptake. These effects were more profound in E4 than E3 mice. Furthermore, the cognitive, metabolic and cerebrovascular responses to an exogenous glucose load showed an apoE isoform-dependent response, with E4, but not E3 mice, acutely benefiting from a spike in blood glucose.

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Cited by

Sorted by citations

Authors
Johnson, L. A., Torres, E. R., Weber Boutros, S., Patel, E., Akinyeke, T., Alkayed, N. J., & Raber, J.
Affiliations
  • University of Kentucky (US)
  • Oregon Health & Science University (US)
  • Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA
Corresponding author
Raber, Jacob
ORCID
Venue
Journal of Cerebral Blood Flow & Metabolism
Publisher
SAGE Publications
Published
2017-12-07
Volume
39
Issue
5
Pages
770-781
ISSN
  • 0271-678X (ISSN-L)
  • 1559-7016
DOI
10.1177/0271678x17746186
PMC
PMC6498752
OpenAlex
W2774482634
Cited by
56
References
13
Citations by year
2026: 4 · 2025: 7 · 2024: 8 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 12 · 2019: 3 · 2018: 4
FWCI
3.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cerebral Blood Flow & Metabolism (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by-nc)
Funders
  • National Institute on Aging (R56AG057495, R21AG043857)
  • National Heart, Lung, and Blood Institute (T32HL094294)
  • National Institute of General Medical Sciences (P20GM103527, P30GM127211)
  • National Institute of Neurological Disorders and Stroke (R01NS108501)
  • National Institute of Environmental Health Sciences (T32ES007060)
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 › Neurological Disease Mechanisms and Treatments
Keywords
APOE ε4, apolipoprotein E3, insulin resistance, cerebrovascular dysfunction, postprandial glucose response, high-fat diet, obesity, age-related cognitive decline, Alzheimer's disease, cerebral blood volume, brain glucose uptake, cognitive impairment
MeSH terms
Animals, Brain, Cerebrovascular Circulation, Cognition, Female, Glucose, Humans, Insulin Resistance, Obesity, Postprandial Period, Mice, Apolipoprotein E3, Apolipoprotein E4, Diet, High-Fat, Cognitive Dysfunction

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