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

Elizabeth S Chan,Christopher Chen,Gregory M Cole,Boon-Seng Wong

doi:10.1038/srep13842

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.

Highlights

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of memory and other cognitive faculties, leading to dementia[1]
At 78 weeks, post-hoc analysis Tukey-Kramer analysis showed that ApoE4xAPP mice had significantly higher Aβ 42/ Aβ 40 ratio than amyloid precursor protein (APP) and ApoE3xAPP mice (Fig. 1)
While its mechanism is still currently unknown, it is certain that apolipoprotein E4 (ApoE4) expression leads to earlier onset of the disease and rapid accumulation of Aβ plaques

Summary

Introduction

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of memory and other cognitive faculties, leading to dementia[1]. Unlike the other two isoforms, ApoE4 exists in a “molten globule” formation, which makes it more prone to proteolytic cleavage. This hinders the protein from carrying out its regular functions and may result in the formation of neurotoxic ApoE4 fragments[6]. Insulin and insulin receptors were markedly reduced in postmortem AD brains, and insulin sensitivity was impaired in the hippocampal formation of AD samples[9,10]. These data indicate that insulin sensitivity is associated with AD, at least at the end stage. The activation of Akt promotes neuronal survival, and is known to contribute to long-term potentiation (LTP) and CREB phosphorylation at serine residue 133 (S133), which are relevant to memory consolidation[12,13]

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Conclusion