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

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

doi:10.1038/srep13842

Cited by 27 publications

(24 citation statements)

References 58 publications

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“…It was reported that the disturbance of insulin signaling was worse in amyloid model mice expressing human apoE4 (ApoE4/APP) which correlates with poorer memory performance, compared with ApoE3/APP mice (Chan et al, 2015; Chan et al, 2016). However, it is still unclear whether Aβ and apoE4 play synergistic or competing roles in disrupting insulin signaling.…”

Section: Discussionmentioning

confidence: 99%

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Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes

Zhao

Liu

Ingelgom

et al. 2017

Neuron

230

224

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SUMMARY Diabetes and impaired brain insulin signaling are linked to the pathogenesis of Alzheimer’s disease (AD). The association between diabetes and AD-associated amyloid pathology is stronger among carriers of the apolipoprotein E (APOE) ε4 gene allele, the strongest genetic risk factor for late-onset AD. Here we report that apoE4 impairs neuronal insulin signaling in human apoE-targeted replacement (TR) mice in an age-dependent manner. High fat diet (HFD) accelerates these effects in apoE4-TR mice at middle age. In primary neurons, apoE4 interacts with insulin receptor and impairs its trafficking by trapping it in the endosomes, leading to impaired insulin signaling and insulin-stimulated mitochondrial respiration and glycolysis. In aging brains, the increased apoE4 aggregation and compromised endosomal function further exacerbate the inhibitory effects of apoE4 on insulin signaling and related functions. Together, our study provides novel mechanistic insights into the pathogenic mechanisms of apoE4 and insulin resistance in AD.

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Section: Discussionmentioning

confidence: 99%

“…However, it is still unclear whether Aβ and apoE4 play synergistic or competing roles in disrupting insulin signaling. It was shown that in the presence of Aβ, apoE4 bound more to Aβ whereas apoE3 bound more to IR (Chan et al, 2015). Our current findings demonstrate that apoE4 has higher binding affinity to IR in the absence of Aβ.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes

Zhao

Liu

Ingelgom

et al. 2017

Neuron

230

224

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“…Ong et al [64] reported a reduction of Akt phosphorylation at Thr308 at 32 weeks and at Ser473 at 72 weeks of age in apoE4-TR mice as compared to apoE3-TR mice. Chan et al [93] reported that in 26-week old mice, there was no difference in the expression and phosphorylation of insulin signaling proteins among APP, APOE3xAPP, and APOE4xAPP mouse brains while when the mice aged to 78 weeks, these proteins were markedly reduced in APP and APOE4xAPP mouse brains.…”

Section: Discussionmentioning

confidence: 99%

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

Koren-Iton

Salomon-Zimri

Smolar

et al. 2020

IJMS

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Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer’s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.

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“…The relationship between amyloid β and insulin resistance is also modulated by ApoE genotype [47]. The interplay between amyloid β, insulin, and ApoE isoforms were investigated using an APP mouse model expressing human ApoE isoforms [48,49]. ApoE4 enhanced the amyloid β-induced impairment of insulin signaling and accelerated the hippocampal-dependent cognitive deficits, as compared with ApoE3 [49].…”

Section: Apolipoprotein E In Metabolism Of Lipid and Glucosementioning

confidence: 99%

“…ApoE4 enhanced the amyloid β-induced impairment of insulin signaling and accelerated the hippocampal-dependent cognitive deficits, as compared with ApoE3 [49]. There was less insulin receptor coimmunoprecipitated with ApoE in brain lysates of APP/ApoE4 mice as compared with that in APP/ApoE3 mice, suggesting a weaker interaction between insulin receptor and ApoE4 as compared with ApoE3 [48]. Because amyloid plaque burden is higher in the ApoE4 mice compared with ApoE3 mice, it is hard to rule out whether the higher amount of amyloid β in the APP/ApoE4 mice actually contributes to the insulin resistance.…”

Section: Apolipoprotein E In Metabolism Of Lipid and Glucosementioning

confidence: 99%

Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease

Liao

Yoon

Kim

2017

Current Opinion in Lipidology

137

100

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Purpose of reviewAPOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease.Recent findingsApoE isoforms have differential effects on amyloid β metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid β clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid β. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid β-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis.SummaryEmerging data suggest that ApoE affects several amyloid β-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease.

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

Cited by 27 publications

References 58 publications

Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes

Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease

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