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Cited by 44Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice

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Ong, Qi-Rui, Chan, Elizabeth S., Lim, Mei-Li, Cole, Gregory M., Wong, Boon-Seng·2014·Scientific Reports
DOI 10.1038/srep03754PMC PMC3894554
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Abstract

Human ApoE4 accelerates memory decline in ageing and in Alzheimer's disease. Although intranasal insulin can improve cognition, this has little effect in ApoE4 subjects. To understand this ApoE genotype-dependent effect, we examined brain insulin signaling in huApoE3 and huApoE4 targeted replacement (TR) mice. At 32 weeks, lower insulin receptor substrate 1 (IRS1) at S636/639 and Akt phosphorylation at T308 were detected in fasting huApoE4 TR mice as compared to fasting huApoE3 TR mice. These changes in fasting huApoE4 TR mice were linked to lower brain glucose content and have no effect on plasma glucose level. However, at 72 weeks of age, these early changes were accompanied by reduction in IRS2 expression, IRS1 phosphorylation at Y608, Akt phosphorylation at S473, and MAPK (p38 and p44/42) activation in the fasting huApoE4 TR mice. The lower brain glucose was significantly associated with higher brain insulin in the aged huApoE4 TR mice. These results show that ApoE4 reduces brain insulin signaling and glucose level leading to higher insulin content.

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Cited by

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Authors
Ong, Q.-R., Chan, E. S., Lim, M.-L., Cole, G. M., & Wong, B.-S.
Affiliations
  • National University of Singapore (SG)
  • University of California, Los Angeles (US)
Corresponding author
Wong, Boon-Seng
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2014-01-17
Volume
4
Issue
1
Pages
3754-3754
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep03754
PMC
PMC3894554
OpenAlex
W2083527523
Cited by
44
References
12
Citations by year
2026: 3 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 6 · 2020: 4 · 2019: 8 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 1 · 2014: 4
FWCI
2.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX000542)
  • Medical Research Council
  • National Medical Research Council (NMRC/ 1148/2008)
  • Biomedical Research Council (BMRC/05/1/21/19/401)
  • National Institute on Aging (P50AG016570, RC1AG035878)
  • National Center for Complementary and Integrative Health (R01AT006816)
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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
APOE ε4, brain insulin signaling, IRS-1, IRS-1 phosphorylation, Akt phosphorylation, insulin receptor substrate 2, MAPK activation, brain glucose, fasting, aging, Alzheimer's disease, intranasal insulin
MeSH terms
Animals, Blood Glucose, Brain, Cholesterol, Glucose, Humans, Insulin, Mice, Transgenic, Receptor, Insulin, Gene Expression, Gene Targeting, Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, Mice, Apolipoprotein E4, Insulin Receptor Substrate Proteins

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