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Cited by 29Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice

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Chan, Elizabeth S, Chen, Christopher, Cole, Gregory M, Wong, Boon-Seng·2015·Scientific Reports
DOI 10.1038/srep13842PMC PMC4561911
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Abstract

It is unclear how human apolipoprotein E4 (ApoE4) increases the risk for Alzheimer’s disease (AD). Although Aβ levels can lead to insulin signaling impairment, these experiments were done in the absence of human ApoE. To examine ApoE role, we crossed the human ApoE-targeted replacement mice with mutant human amyloid precursor protein (APP) mice. In 26 week old mice with lower Aβ levels, the expression and phosphorylation of insulin signaling proteins remained comparable among APP, ApoE3xAPP and ApoE4xAPP mouse brains. When the mice aged to 78 weeks, these proteins were markedly reduced in APP and ApoE4xAPP mouse brains. While Aβ can bind to insulin receptor, how ApoE isoforms modulate this interaction remains unknown. Here, we showed that ApoE3 had greater association with insulin receptor as compared to ApoE4, regardless of Aβ42 concentration. In contrast, ApoE4 bound more Aβ42 with increasing peptide levels. Using primary hippocampal neurons, we showed that ApoE3 and ApoE4 neurons are equally sensitive to physiological levels of insulin. However, in the presence of Aβ42, insulin failed to elicit a downstream response only in ApoE4 hippocampal neurons. Taken together, our data show that ApoE genotypes can modulate this Aβ-mediated insulin signaling impairment.

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  • Amyloid plaque burden is higher in APP/ApoE4 mice compared with APP/ApoE3 mice.

    “Because amyloid plaque burden is higher in the ApoE4 mice compared with ApoE3 mice, it is hard to rule out whether the higher amount of amyloid β in the APP/ApoE4 mice actually contributes to the insulin resistance.”

    From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [48]

    The Results section (‘Aβ content in the aging ApoE-APP mice’; page unavailable) reports a significantly higher Aβ42/Aβ40 ratio in ApoE4xAPP than ApoE3xAPP mice at 78 weeks, but no significant difference at 26 weeks. The paper describes greater Aβ accumulation in the older ApoE4xAPP mice; these passages do not establish a higher measured plaque burden across ages. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The interaction between insulin receptor and ApoE4 is weaker than between insulin receptor and ApoE3.

    “There was less insulin receptor coimmunoprecipitated with ApoE in brain lysates of APP/ApoE4 mice as compared with that in APP/ApoE3 mice, suggesting a weaker interaction between insulin receptor and ApoE4 as compared with ApoE3 [48].”

    From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [48]

  • There was less insulin receptor coimmunoprecipitated with ApoE in brain lysates of APP/ApoE4 mice compared with APP/ApoE3 mice.

    “There was less insulin receptor coimmunoprecipitated with ApoE in brain lysates of APP/ApoE4 mice as compared with that in APP/ApoE3 mice, suggesting a weaker interaction between insulin receptor and ApoE4 as compared with ApoE3 [48].”

    From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [48]

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Research works printed but not linked: 44

  1. Karch C. M., Cruchaga C. & Goate A. M. Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83, 11– 26 (2014). 24991952 PMC4120741
  2. Corder E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921– 923 (1993). 8346443
  3. Mahley R. W., Weisgraber K. H. & Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci USA 103, 5644– 5651 (2006). 16567625 PMC1414631
  4. Weisgraber K. H., Rall S. C. Jr. & Mahley R. W. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem 256, 9077– 9083 (1981). 7263700
  5. Huang Y. et al. Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci USA 98, 8838– 8843 (2001). 11447277 PMC37522
  6. Hoyer S. The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review. J Neural Transm 109, 991– 1002 (2002). 12111436
  7. Talbot K. et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 122, 1316– 1338 (2012). 22476197 PMC3314463
  8. Duarte A. I., Moreira P. I. & Oliveira C. R. I nsulin in Central Nervous System: More than Just a Peripheral Hormone. J Aging Res 2012, 21 (2012). PMC3303591 22500228
  9. Zhao L. et al. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer’s disease intervention. J Neurosci 24, 11120– 11126 (2004). 15590928 PMC6730264
  10. Cole A. R., Astell A., Green C. & Sutherland C. Molecular connexions between dementia and diabetes. Neurosci Biobehav Rev 31, 1046– 1063 (2007). 17544131
  11. Filippi B. M., Mighiu P. I. & Lam T. K. Is insulin action in the brain clinically relevant? Diabetes 61, 773– 775 (2012). 22442296 PMC3314359
  12. Reger M. A. et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 27, 451– 458 (2006). 15964100
  13. Reger M. A. et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 70, 440– 448 (2008). 17942819
  14. Craft S. et al. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology 28, 809– 822 (2003). 12812866
  15. Bomfim T. R. et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Abeta oligomers. J Clin Invest 122, 1339– 1353 (2012). 22476196 PMC3314445
  16. Townsend M., Mehta T. & Selkoe D. J. Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem 282, 33305– 33312 (2007). 17855343
  17. Knouff C. et al. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Invest 103, 1579– 1586 (1999). 10359567 PMC408371
  18. Games D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373, 523– 527 (1995). 7845465
  19. Rockenstein E. M. et al. Levels and alternative splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer’s disease. J Biol Chem 270, 28257– 28267 (1995). 7499323
  20. Mahley R. W. & Rall S. C. Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1, 507– 537 (2000). 11701639
  21. Holtzman D. M., Herz J. & Bu G. Apolipoprotein e and apolipoprotein e receptors: normal biology and roles in Alzheimer disease. Cold Spring Harbor perspectives in medicine 2, a006312 (2012). 22393530 PMC3282491
  22. Grootendorst J. et al. Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior. Behav Brain Res 159, 1– 14 (2005). 15794991
  23. Kobayashi D. T. & Chen K. S. Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer’s disease. Genes Brain Behav 4, 173– 196 (2005). 15810905
  24. Wang J., Tanila H., Puolivali J., Kadish I. & van Groen T. Gender differences in the amount and deposition of amyloidbeta in APPswe and PS1 double transgenic mice. Neurobiol Dis 14, 318– 327 (2003). 14678749
  25. Altmann A., Tian L., Henderson V. W., Greicius M. D. & Alzheimer’s Disease Neuroimaging Initiative, I. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol 75, 563– 573 (2014). 24623176 PMC4117990
  26. Koyama A. et al. Plasma amyloid-beta as a predictor of dementia and cognitive decline: a systematic review and meta-analysis. Arch Neurol 69, 824– 831 (2012). 22451159 PMC3772635
  27. Masters C. L. & Selkoe D. J. Biochemistry of amyloid beta-protein and amyloid deposits in Alzheimer disease. Cold Spring Harbor perspectives in medicine 2, a006262 (2012). 22675658 PMC3367542
  28. Selkoe D. J. Alzheimer’s disease. Cold Spring Harb Perspect Biol 3, 7 (2011). PMC3119915 21576255
  29. Bien-Ly N. et al. C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-beta (Abeta) and acts in concert with Abeta to elicit neuronal and behavioral deficits in mice. Proc Natl Acad Sci USA 108, 4236– 4241 (2011). 21368138 PMC3053957
  30. Xu P. T. et al. Sialylated human apolipoprotein E (apoEs) is preferentially associated with neuron-enriched cultures from APOE transgenic mice. Neurobiol Dis 6, 63– 75 (1999). 10078974
  31. Xie L. et al. Alzheimer’s beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci 22, RC221 (2002). 12006603 PMC6757630
  32. Zhao W. Q. et al. Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric a{beta}. J Biol Chem 284, 18742– 18753 (2009). 19406747 PMC2707198
  33. Hong J., Zhang H., Kawase-Koga Y. & Sun T. MicroRNA function is required for neurite outgrowth of mature neurons in the mouse postnatal cerebral cortex. Front Cell Neurosci 7, 151 (2013). 24062642 PMC3772315
  34. Loo D. T. et al. Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci USA 90, 7951– 7955 (1993). 8367446 PMC47265
  35. Nicholson A. M. & Ferreira A. Increased membrane cholesterol might render mature hippocampal neurons more susceptible to beta-amyloid-induced calpain activation and tau toxicity. J Neurosci 29, 4640– 4651 (2009). 19357288 PMC2705291
  36. Tai L. M. et al. Amyloid-beta Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in vivo. J Biol Chem 289, 30538– 30555 (2014). 25217640 PMC4215234
  37. LaDu M. J. et al. Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem 269, 23403– 23406 (1994). 8089103
  38. Sanan D. A. et al. Apolipoprotein E associates with beta amyloid peptide of Alzheimer’s disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J Clin Invest 94, 860– 869 (1994). 8040342 PMC296168
  39. Strittmatter W. J. et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 90, 8098– 8102 (1993). 8367470 PMC47295
  40. Garai K., Verghese P. B., Baban B., Holtzman D. M. & Frieden C. The binding of apolipoprotein E to oligomers and fibrils of amyloid-beta alters the kinetics of amyloid aggregation. Biochemistry 53, 6323– 6331 (2014). 25207746 PMC4196732
  41. Verghese P. B. et al. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci USA 110, E1807– 1816 (2013). 23620513 PMC3651443
  42. Ong Q. R., Chan E. S., Lim M. L., Cole G. M. & Wong B. S. Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice. Sci Rep 4, 3754 (2014). 24435134 PMC3894554
  43. Yong S. M., Lim M. L., Low C. M. & Wong B. S. Reduced neuronal signaling in the ageing apolipoprotein-E4 targeted replacement female mice. Sci Rep 4, 6580 (2014). 25301084 PMC4192620
  44. Sundaram J. R. et al. Cdk5/p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurodegeneration. J Neurosci 32, 1020– 1034 (2012). 22262900 PMC6621136

Cited by

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Authors
Chan, E. S., Chen, C., 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
2015-09-08
Volume
5
Issue
1
Pages
13842-13842
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep13842
PMC
PMC4561911
OpenAlex
W1463613178
Cited by
29
References
14
Citations by year
2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 4
FWCI
3.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National University Health System (NUHSRO/2011/005/STB/B2B-01)
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, APOE ε4, insulin receptor, insulin signaling, amyloid precursor protein, amyloid-beta 42, Alzheimer's disease, hippocampal neurons, receptor binding
MeSH terms
Aging, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Humans, Insulin, Mice, Transgenic, Mutation, Phosphorylation, Protein Binding, Receptor, Insulin, Signal Transduction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Pyramidal Cells, Protein Isoforms, Proto-Oncogene Proteins c-akt, Mice, Apolipoprotein E4, Insulin Receptor Substrate Proteins

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