Differential Binding of Human ApoE Isoforms to Insulin Receptor is Associated with Aberrant Insulin Signaling in AD Brain Samples
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.
KeywordsInsulin signaling ApoE Amyloid pathology Akt signaling Alzheimer’s disease
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.
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.
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.
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