title: Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells.
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.
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H8M5, Canada.|Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, K1A0R6, Canada.
authors.forename: Dema
authors.initials: D
authors.lastname: Najem
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H8M5, Canada.|Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, K1A0R6, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Bamji-Mirza
authors.affiliation: Beijing Hospital, Institute of Geriatrics-Chinese Health Ministry, Beijing, 100730, China.
authors.forename: Ze
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H8M5, Canada. Wandong.Zhang@nrc.ca.|Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, K1A0R6, Canada. Wandong.Zhang@nrc.ca.
authors.forename: Wandong
authors.initials: W
authors.lastname: Zhang
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007328:Insulin; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human
keywords: Alzheimer’s disease; Aβ peptides; Cholesterol synthesis pathway; Insulin resistance; Insulin signaling; Pro-inflammatory response