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Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells

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Abstract

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) toxicity, tau pathology, insulin resistance, neuroinflammation, and dysregulation of cholesterol homeostasis, all of which play roles in neurodegeneration. Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes. In this study, we investigated possible relationships among insulin signaling and cholesterol biosynthesis, along with the effects of Aβ42 on these pathways in vitro. We found that neuroblastoma 2a (N2a) cells transfected with the human gene encoding amyloid-β protein precursor (AβPP) (N2a-AβPP) produced Aβ and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment, and by increased phosphorylation of insulin receptor subunit-1 at serine 612 (p-IRS-S612) as compared to parental N2a cells. Treatment of human neuroblastoma SH-SY5Y cells with Aβ42 also increased p-IRS-S612, suggesting that Aβ42 is responsible for insulin resistance. The insulin resistance was alleviated when N2a-AβPP cells were treated with higher insulin concentrations. Insulin increased Aβ release from N2a-AβPP cells, by which it may promote Aβ clearance. Insulin increased cholesterol-synthesis gene expression in SH-SY5Y and N2a cells, including 24-dehydrocholesterol reductase (DHCR24) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) through sterol-regulatory element-binding protein-2 (SREBP2). While Aβ42-treated SH-SY5Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses, they also showed down-regulation of neuro-protective/anti-inflammatory DHCR24. These results suggest that Aβ42 may cause insulin resistance, activate JNK for c-Jun phosphorylation, and lead to dysregulation of cholesterol homeostasis, and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote Aβ release for clearance from neural cells.

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Acknowledgements

This work was supported by CIHR Grants (109606, 106886, and TAD 125698) and an Ontario Graduate Scholarship, an Admission Scholarship, and an Excellence Scholarship from the University of Ottawa. This work was conducted at the National Research Council of Canada. We thank Dr. Hsiao-Huei Chen and Dr. Ross Milne at the University of Ottawa for their critical comments and support of the study, and Dr. Huaxi Xu at the Sanford-Burnham Medical Research Institute for providing the N2a-AβPP cells.

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  1. Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H8M5, Canada

    Dema Najem, Michelle Bamji-Mirza & Wandong Zhang

  2. Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, K1A0R6, Canada

    Dema Najem, Michelle Bamji-Mirza & Wandong Zhang

  3. Beijing Hospital, Institute of Geriatrics-Chinese Health Ministry, Beijing, 100730, China

    Ze Yang

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  1. Dema Najem
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Najem, D., Bamji-Mirza, M., Yang, Z. et al. Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells. Neurosci. Bull. 32, 227–238 (2016). https://doi.org/10.1007/s12264-016-0034-9

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