Vol.:(0123456789) 1 3 NeuroMolecular Medicine https://doi.org/10.1007/s12017-018-8480-3 ORIGINAL PAPER Diferential Binding of Human ApoE Isoforms to Insulin Receptor is Associated with Aberrant Insulin Signaling in AD Brain Samples Elizabeth S. Chan 1  · Christopher Chen 2,4  · Tuck Wah Soong 1,3  · Boon‑Seng Wong 1,5 Received: 1 January 2018 / Accepted: 3 February 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 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 defcits in the presence of amyloid beta (Aβ). However, these reports were not conducted with clinical samples that more accurately refect human disease. In this study, we investigated the efect 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 diference in IR binding and efect on protein expression downstream of the IR may afect onset and progression of AD. Keywords Insulin signaling · ApoE · Amyloid pathology · Akt signaling · Alzheimer’s disease Introduction Alzheimer’s disease (AD) is a devastating neurodegenera- tive disease, characterized by the presence of extracellular deposits of amyloid plaques, and intracellular neurofbrillary tangles of hyperphosphorylated tau (Huang and Mucke 2012; Palop and Mucke 2010). The clinical manifestation of the disease usually starts with patients experiencing memory loss, and as the disease advances, atrophy of the brain occurs with substantial gray matter loss (Selkoe 2011), accompa- nied by the progressive decline in cognition and function, ultimately leading to dementia (Huang and Mucke 2012; Palop and Mucke 2010; Selkoe 2011). The majority of AD patients are sporadic cases, and ApoE4 is the strongest genetic risk factor for sporadic AD (> 60 years old) (Corder et al. 1993). Human ApoE exists in three isoforms, namely the ApoE2 (cys112, cys158), ApoE3 (cys112, arg158) and ApoE4 (arg112, arg158), and they dif- fer from each other by having either a cysteine or an arginine residue at position 112 and position 158 (Mahley and Huang 2012). Unlike ApoE3, which is expressed in ~ 80% of the population, ApoE4 is expressed in ~ 14% of the population. However, ApoE4 carriers account for > 50% of all sporadic patients and accelerates onset of AD (Mahley and Huang 2012). Although the association between ApoE4 and AD has been extensively studied, their mechanism remains elu- sive. Hence, the underlying pathways associated with ApoE4 * Boon-Seng Wong BoonSeng.Wong@singaporetech.edu.sg 1 Departments of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore 2 Departments of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore 3 Memory Networks Program, Neurobiology and Ageing Program, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore 4 Memory Ageing and Cognition Centre, National University Health System (NUHS), Singapore 117599, Singapore 5 Health and Social Sciences Cluster, Singapore Institute of Technology, 10 Dover Drive, Singapore 138683, Singapore