Differential Binding of Human ApoE Isoforms to Insulin Receptor is Associated with Aberrant Insulin Signaling in AD Brain Samples
Tóm tắt
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.
Tài liệu tham khảo
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.
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.
Beffert, U., & Poirier, J. (1998). ApoE associated with lipid has a reduced capacity to inhibit beta-amyloid fibril formation. NeuroReport, 9, 3321–3323.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Craft, S., & Watson, G. S. (2004). Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurology, 3, 169–178.
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.
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.
de la Monte, S. M. (2009). Insulin resistance and Alzheimer’s disease. BMB Reports, 42, 475–481.
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.
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.
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.
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.
Hardingham, G. E., & Bading, H. (2003). The Yin and Yang of NMDA receptor signalling. Trends in Neurosciences, 26, 81–89.
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.
Hemmings, B. A., & Restuccia, D. F. (2012). PI3K-PKB/Akt pathway. Cold Spring Harbor Perspectives in Biology, 4, a011189.
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.
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.
Huang, Y., & Mucke, L. (2012). Alzheimer mechanisms and therapeutic strategies. Cell, 148, 1204–1222.
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.
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.
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.
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.
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.
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.
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.
Mahley, R. W., & Huang, Y. (2012). Apolipoprotein e sets the stage: Response to injury triggers neuropathology. Neuron, 76, 871–885.
Malinow, R., & Malenka, R. C. (2002). AMPA receptor trafficking and synaptic plasticity. Annual Review of Neuroscience, 25, 103–126.
Manning, B. D., & Cantley, L. C. (2007). AKT/PKB signaling: Navigating downstream. Cell, 129, 1261–1274.
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.
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.
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.
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.
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.
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.
Selkoe, D. J. (2011). Alzheimer’s disease. Cold Spring Harbor Perspectives in Biology, 3, 7.
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.
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.
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.
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.
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.
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.
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.
Zhao, W. Q., & Alkon, D. L. (2001). Role of insulin and insulin receptor in learning and memory. Molecular and Cellular Endocrinology, 177, 125–134.
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.
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.
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.