Differential Binding of Human ApoE Isoforms to Insulin Receptor is Associated with Aberrant Insulin Signaling in AD Brain Samples

  • Elizabeth S. Chan
  • Christopher Chen
  • Tuck Wah Soong
  • Boon-Seng Wong
Original Paper
  • 3 Downloads

Abstract

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), where inheritance of this isoform predisposes development of AD in a gene dose-dependent manner. Although the mode of action of ApoE4 on AD onset and progression remains unknown, we have previously shown that ApoE4, and not ApoE3 expression, resulted in insulin signaling deficits in the presence of amyloid beta (Aβ). However, these reports were not conducted with clinical samples that more accurately reflect human disease. In this study, we investigated the effect of ApoE genotype on the insulin signaling pathway in control and AD human brain samples. We found that targets of the insulin signaling pathway were attenuated in AD cases, regardless of ApoE isoform. We also found a decrease in GluR1 subunit expression, and an increase NR2B subunit expression in AD cases, regardless of ApoE isoform. Lastly, we observed that more insulin receptor (IR) was immunoprecipitated in control cases, and more Aβ was immunoprecipitated with AD cases. But, when comparing among AD cases, we found that more IR was immunoprecipitated with ApoE3 than ApoE4, and more Aβ was immunoprecipitated with ApoE4 than ApoE3. Our results suggest that the difference in IR binding and effect on protein expression downstream of the IR may affect onset and progression of AD.

Keywords

Insulin signaling ApoE Amyloid pathology Akt signaling Alzheimer’s disease 

Notes

Acknowledgements

We thank Drs. Edward Koo and Eliezer Masliah from the Alzheimer Disease Research Center (ADRC) at the University of California San Diego (UCSD) for providing the human brain samples. This work was supported by grants to BSW from the National University Health System (NUHSRO/2011/005/STB/B2B-01) and to TWS from the National Medical Research Council (NMRC/CBRG/0090/2015). ESC was supported by graduate scholarships from Singapore Ministry of Education. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author Contributions

E.S.C. performed the experiments. E.S.C. and B.S.W. conceived and designed the experiments, and analyzed the data. E.S.C, S.T.W., C.C. and B.S.W. wrote the paper.

Compliance with Ethical Standards

Conflict of interest

The authors have declared that no competing interests exist.

Ethical Approval

The human postmortem frontal cortex samples were provided by the Alzheimer Disease Research Center (ADRC) at the University of California San Diego (UCSD). Patient consent had been administered at UCSD ADRC. The samples were provided in a coded fashion. Research has been conducted according to the principles expressed in the Declaration of Helsinki. Analysis of the de-identified samples was performed with research approval by the National University of Singapore (NUS) Institutional Review Board.

References

  1. Bales, K. R., Liu, F., Wu, S., Lin, S., Koger, D., DeLong, C., et al. (2009). Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice. Journal of Neuroscience, 29, 6771–6779.CrossRefPubMedGoogle Scholar
  2. Bales, K. R., Verina, T., Cummins, D. J., Du, Y., Dodel, R. C., Saura, J., et al. (1999). Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences USA, 96, 15233–15238.CrossRefGoogle Scholar
  3. Beffert, U., & Poirier, J. (1998). ApoE associated with lipid has a reduced capacity to inhibit beta-amyloid fibril formation. NeuroReport, 9, 3321–3323.CrossRefPubMedGoogle Scholar
  4. Bien-Ly, N., Andrews-Zwilling, Y., Xu, Q., Bernardo, A., Wang, C., & Huang, Y. (2011). 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. Proceedings of the National Academy of Sciences USA, 108, 4236–4241.CrossRefGoogle Scholar
  5. Bien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y., & Huang, Y. (2012). Reducing human apolipoprotein E levels attenuates age-dependent Abeta accumulation in mutant human amyloid precursor protein transgenic mice. Journal of Neuroscience, 32, 4803–4811.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bomfim, T. R., Forny-Germano, L., Sathler, L. B., Brito-Moreira, J., Houzel, J. C., Decker, H., et al. (2012). An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease—associated Abeta oligomers. The Journal of Clinical Investigation, 122, 1339–1353.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chan, E. S., Chan, C., Cole, G. M., & Wong, B. S. (2015). Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice. Scientific Reports, 5, 13842.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chan, E. S., Shetty, M. S., Sajikumar, S., Chen, C., Soong, T. W., & Wong, B.-S. (2016). ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer’s disease mouse model. Scientific Reports, 6, 26119.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chua, L. M., Lim, M. L., Chong, P. R., Hu, Z. P., Cheung, N. S., & Wong, B. S. (2012). Impaired neuronal insulin signaling precedes A beta(42) accumulation in female A beta PPsw/PS1 Delta E9 Mice. Journal of Alzheimer’s Disease, 29, 783–791.PubMedGoogle Scholar
  10. Cole, G. M., & Frautschy, S. A. (2007). The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer’s disease. Experimental Gerontology, 42, 10–21.CrossRefPubMedGoogle Scholar
  11. Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261, 921–923.CrossRefPubMedGoogle Scholar
  12. Correia, S. C., Santos, R. X., Perry, G., Zhu, X., Moreira, P. I., & Smith, M. A. (2011). Insulin-resistant brain state: The culprit in sporadic Alzheimer’s disease? Ageing Research Reviews, 10, 264–273.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Craft, S., Asthana, S., Cook, D. G., Baker, L. D., Cherrier, M., Purganan, K., et al. (2003). Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: Interactions with apolipoprotein E genotype. Psychoneuroendocrinology, 28, 809–822.CrossRefPubMedGoogle Scholar
  14. Craft, S., Baker, L. D., Montine, T. J., Minoshima, S., Watson, G. S., Claxton, A., et al. (2012). Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Archives of Neurology, 69, 29–38.CrossRefPubMedGoogle Scholar
  15. Craft, S., & Watson, G. S. (2004). Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurology, 3, 169–178.CrossRefPubMedGoogle Scholar
  16. Cramer, P. E., Cirrito, J. R., Wesson, D. W., Lee, C. Y., Karlo, J. C., Zinn, A. E., et al. (2012). ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science, 335, 1503–1506.CrossRefPubMedPubMedCentralGoogle Scholar
  17. De Felice, F. G., Vieira, M. N., Bomfim, T. R., Decker, H., Velasco, P. T., Lambert, M. P., et al. (2009). Protection of synapses against Alzheimer’s-linked toxins: Insulin signaling prevents the pathogenic binding of Abeta oligomers. Proceedings of the National Academy of Sciences USA, 106, 1971–1976.CrossRefGoogle Scholar
  18. de la Monte, S. M. (2009). Insulin resistance and Alzheimer’s disease. BMB Reports, 42, 475–481.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Decker, H., Lo, K. Y., Unger, S. M., Ferreira, S. T., & Silverman, M. A. (2010). Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3beta in primary cultured hippocampal neurons. Journal of Neuroscience, 30, 9166–9171.CrossRefPubMedGoogle Scholar
  20. Frolich, L., Blum-Degen, D., Bernstein, H. G., Engelsberger, S., Humrich, J., Laufer, S., et al. (1998). Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. Journal of Neural Transmission, 105, 423–438.CrossRefPubMedGoogle Scholar
  21. Garai, K., Verghese, P. B., Baban, B., Holtzman, D. M., & Frieden, C. (2014). The binding of apolipoprotein E to oligomers and fibrils of amyloid-beta alters the kinetics of amyloid aggregation. Biochemistry, 53, 6323–6331.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Gual, P., Le Marchand-Brustel, Y., & Tanti, J. F. (2005). Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie, 87, 99–109.CrossRefPubMedGoogle Scholar
  23. Hardingham, G. E., & Bading, H. (2003). The Yin and Yang of NMDA receptor signalling. Trends in Neurosciences, 26, 81–89.CrossRefPubMedGoogle Scholar
  24. Hayashi, Y., Shi, S. H., Esteban, J. A., Piccini, A., Poncer, J. C., & Malinow, R. (2000). Driving AMPA receptors into synapses by LTP and CaMKII: Requirement for GluR1 and PDZ domain interaction. Science, 287, 2262–2267.CrossRefPubMedGoogle Scholar
  25. Hemmings, B. A., & Restuccia, D. F. (2012). PI3K-PKB/Akt pathway. Cold Spring Harbor Perspectives in Biology, 4, a011189.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Holscher, C. (2014). First clinical data of the neuroprotective effects of nasal insulin application in patients with Alzheimer’s disease. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 10, S33–S37.CrossRefGoogle Scholar
  27. Hoyer, S. (2002). The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review. Journal Of Neural Transmission, 109, 991–1002.CrossRefPubMedGoogle Scholar
  28. Huang, Y., & Mucke, L. (2012). Alzheimer mechanisms and therapeutic strategies. Cell, 148, 1204–1222.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Huynh, T.-P. V., Liao, F., Francis, C. M., Robinson, G. O., Serrano, J. R., Jiang, H., et al. (2017). Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of β-amyloidosis. Neuron, 96(1013–1023), e1014.Google Scholar
  30. Lacor, P. N., Buniel, M. C., Furlow, P. W., Clemente, A. S., Velasco, P. T., Wood, M., et al. (2007). Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. Journal of Neuroscience, 27, 796–807.CrossRefPubMedGoogle Scholar
  31. LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S., & Frail, D. E. (1994). Isoform-specific binding of apolipoprotein E to beta-amyloid. Journal of Biological Chemistry, 269, 23403–23406.PubMedGoogle Scholar
  32. Lee, C. C., Kuo, Y. M., Huang, C. C., & Hsu, K. S. (2009). Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. Neurobiology of Aging, 30, 377–387.CrossRefPubMedGoogle Scholar
  33. Li, M., Zhang, D. Q., Wang, X. Z., & Xu, T. J. (2011). NR2B-containing NMDA receptors promote neural progenitor cell proliferation through CaMKIV/CREB pathway. Biochemical and Biophysical Research Communications, 411, 667–672.CrossRefPubMedGoogle Scholar
  34. Liu, C.-C., Zhao, N., Fu, Y., Wang, N., Linares, C., Tsai, C.-W., et al. (2017). ApoE4 accelerates early seeding of amyloid pathology. Neuron, 96(1024–1032), e1023.Google Scholar
  35. Liu, Z., Zhao, W., Xu, T., Pei, D., & Peng, Y. (2010). Alterations of NMDA receptor subunits NR1, NR2A and NR2B mRNA expression and their relationship to apoptosis following transient forebrain ischemia. Brain Research, 1361, 133–139.CrossRefPubMedGoogle Scholar
  36. Mahley, R. W., & Huang, Y. (2012). Apolipoprotein e sets the stage: Response to injury triggers neuropathology. Neuron, 76, 871–885.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Malinow, R., & Malenka, R. C. (2002). AMPA receptor trafficking and synaptic plasticity. Annual Review of Neuroscience, 25, 103–126.CrossRefPubMedGoogle Scholar
  38. Manning, B. D., & Cantley, L. C. (2007). AKT/PKB signaling: Navigating downstream. Cell, 129, 1261–1274.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Myers, M. G., Jr., Grammer, T. C., Wang, L. M., Sun, X. J., Pierce, J. H., Blenis, J., et al. (1994). Insulin receptor substrate-1 mediates phosphatidylinositol 3′-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. Journal of Biological Chemistry, 269, 28783–28789.PubMedGoogle Scholar
  40. Nistico, R., Cavallucci, V., Piccinin, S., Macri, S., Pignatelli, M., Mehdawy, B., et al. (2012). Insulin receptor beta-subunit haploinsufficiency impairs hippocampal late-phase LTP and recognition memory. Neuromolecular Medicine, 14, 262–269.CrossRefPubMedGoogle Scholar
  41. Ong, Q. R., Chan, E. S., Lim, M. L., Cole, G. M., & Wong, B. S. (2014). Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice. Sci Rep, 4, 3754.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Palop, J. J., & Mucke, L. (2010). Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: From synapses toward neural networks. Nature Neuroscience, 13, 812–818.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Roselli, F., Tirard, M., Lu, J., Hutzler, P., Lamberti, P., Livrea, P., et al. (2005). Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. Journal of Neuroscience, 25, 11061–11070.CrossRefPubMedGoogle Scholar
  44. Sanan, D. A., Weisgraber, K. H., Russell, S. J., Mahley, R. W., Huang, D., Saunders, A., et al. (1994). Apolipoprotein E associates with beta amyloid peptide of Alzheimer’s disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. The Journal of Clinical Investigation, 94, 860–869.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Selkoe, D. J. (2011). Alzheimer’s disease. Cold Spring Harbor Perspectives in Biology, 3, 7.CrossRefGoogle Scholar
  46. Tai, L. M., Bilousova, T., Jungbauer, L., Roeske, S. K., Youmans, K. L., Yu, C., et al. (2013). Levels of soluble apolipoprotein E/amyloid-beta (Abeta) complex are reduced and oligomeric Abeta increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. Journal of Biological Chemistry, 288, 5914–5926.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Tai, L. M., Koster, K. P., Luo, J., Lee, S. H., Wang, Y. T., Collins, N. C., et al. (2014). Amyloid-beta pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo. Journal of Biological Chemistry, 289, 30538–30555.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Talbot, K., Wang, H. Y., Kazi, H., Han, L. Y., Bakshi, K. P., Stucky, A., et al. (2012). Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. Journal of Clinical Investigation, 122, 1316–1338.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Townsend, M., Mehta, T., & Selkoe, D. J. (2007). Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. Journal of Biological Chemistry, 282, 33305–33312.CrossRefPubMedGoogle Scholar
  50. Verdier, Y., Zarandi, M., & Penke, B. (2004). Amyloid beta-peptide interactions with neuronal and glial cell plasma membrane: binding sites and implications for Alzheimer’s disease. Journal of Peptide Science, 10, 229–248.CrossRefPubMedGoogle Scholar
  51. Verghese, P. B., Castellano, J. M., & Holtzman, D. M. (2011). Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurology, 10, 241–252.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Xie, L., Helmerhorst, E., Taddei, K., Plewright, B., Van Bronswijk, W., & Martins, R. (2002). Alzheimer’s beta-amyloid peptides compete for insulin binding to the insulin receptor. The Journal of Neuroscience, 22, RC221.PubMedGoogle Scholar
  53. Zhao, W. Q., & Alkon, D. L. (2001). Role of insulin and insulin receptor in learning and memory. Molecular and Cellular Endocrinology, 177, 125–134.CrossRefPubMedGoogle Scholar
  54. Zhao, W. Q., De Felice, F. G., Fernandez, S., Chen, H., Lambert, M. P., Quon, M. J., et al. (2008). Amyloid beta oligomers induce impairment of neuronal insulin receptors. The FASEB Journal, 22, 246–260.CrossRefPubMedGoogle Scholar
  55. Zhao, N., Liu, C.-C., Van Ingelgom, A. J., Martens, Y. A., Linares, C., Knight, J. A., et al. (2017). Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron, 96(115–129), e115.CrossRefGoogle Scholar
  56. Zhao, L., Teter, B., Morihara, T., Lim, G. P., Ambegaokar, S. S., Ubeda, O. J., et al. (2004). Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: Implications for Alzheimer’s disease intervention. Journal of Neuroscience, 24, 11120–11126.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Elizabeth S. Chan
    • 1
  • Christopher Chen
    • 2
    • 4
  • Tuck Wah Soong
    • 1
    • 3
  • Boon-Seng Wong
    • 1
    • 5
  1. 1.Departments of Physiology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  2. 2.Departments of Pharmacology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  3. 3.Memory Networks Program, Neurobiology and Ageing Program, Life Sciences InstituteNational University of SingaporeSingaporeSingapore
  4. 4.Memory Ageing and Cognition CentreNational University Health System (NUHS)SingaporeSingapore
  5. 5.Health and Social Sciences ClusterSingapore Institute of TechnologySingaporeSingapore

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