Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology.

Amit Koren-Iton,Joab Chapman,Efrat Shavit-Stein,Shiran Salomon-Zimri,Alex Smolar,Daniel M Michaelson,Amir Dori

doi:10.3390/ijms21041289

Amit Koren-Iton, Joab Chapman + Show 5 more

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https://doi.org/10.3390/ijms21041289

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Abstract

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.

Highlights

The present study examined the effects of the apolipoprotein E (APOE) genotype and high-fat diet (HFD) on glucose metabolism and insulin resistance, and the extent to which they are associated with peripheral and central pathologies
Complementary measurements of insulin resistance and insulin levels revealed that the impairment of glucose tolerance in apolipoprotein E4 (apoE4) mice maintained on a control diet is parallel to impairments in insulin tolerance and insulin secretion
Behavioral cognitive and sensorimotor measurements revealed a similar pattern to that obtained in the glucose tolerance measurements, in which under basal conditions, apoE4 mice are impaired relative to apoE3 mice, and the HFD induces pathological behavioral consequences in apoE3 mice, rendering them similar to apoE4 mice whose behavior was not affected by HFD

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, an age-related neurodegenerative disorder affecting more than 50 million people worldwide [1,2] It is clinically characterized by progressive deterioration of cognition, loss of insight, judgment, language, and changes in behavior and, in late stages, physical functioning [3]. There are three main alleles of the apolipoprotein E, termed apoE2, apoE3, and apoE4, of which the ε4 gene allele (apoE4) has been found to be the most prevalent genetic risk factor for AD [11,12,14] The frequency of this allele in AD patients is over 50%, whereas in the general population its frequency is about 25% [15]. It has been shown that carrying the apoE ε4 allele has a larger deleterious effect on neurodegeneration, synaptic plasticity, and adult neurogenesis, and on cognitive performance in females more than males [18]

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