A\u3b2-induced insulin resistance and the effects of insulin on the cholesterol synthesis pathway and A\u3b2 secretion in neural cells

Alzheimer\u2019s disease (AD) is characterized by amyloid-\u3b2 (A\u3b2) 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 A\u3b242 on these pathways in vitro. We found that neuroblastoma 2a (N2a) cells transfected with the human gene encoding amyloid-\u3b2 protein precursor (A\u3b2PP) (N2a-A\u3b2PP) produced A\u3b2 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 A\u3b242 also increased p-IRS-S612, suggesting that A\u3b242 is responsible for insulin resistance. The insulin resistance was alleviated when N2a-A\u3b2PP cells were treated with higher insulin concentrations. Insulin increased A\u3b2 release from N2a-A\u3b2PP cells, by which it may promote A\u3b2 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 A\u3b242-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 A\u3b242 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 A\u3b2 release for clearance from neural cells.Peer reviewed: YesNRC publication: Ye