Dema Najem;Michelle Bamji-Mirza;Ze Yang;Wandong Zhang;Faculty of Medicine,University of Ottawa;Human Health Therapeutics,National Research Council of Canada;Beijing Hospital,Institute of Geriatrics-Chinese Health Ministry;
Faculty of Medicine,University of Ottawa;Human Health Therapeutics,National Research Council of Canada;Beijing Hospital,Institute of Geriatrics-Chinese Health Ministry;
Alzheimer's disease(AD) is characterized by amyloid-b(Ab) 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 Ab42 on these pathways in vitro.We found that neuroblastoma 2a(N2a) cells transfected with the human gene encoding amyloid-b protein precursor(Ab PP)(N2aAb PP) produced Ab 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 N2 a cells.Treatment of human neuroblastoma SH-SY5 Y cells with Ab42 also increased p-IRS-S612,suggesting that Ab42 is responsible for insulin resistance.The insulin resistance was alleviated when N2a-Ab PP cells were treated with higher insulin concentrations.Insulin increased Ab release from N2 aAb PP cells,by which it may promote Ab clearance.Insulin increased cholesterol-synthesis gene expression in SHSY5 Y and N2 a cells,including 24-dehydrocholesterol reductase(DHCR24) and 3-hydroxy-3-methyl-glutaryl-Co A reductase(HMGCR) through sterol-regulatory element-binding protein-2(SREBP2).While Ab42-treated SH-SY5 Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses,they also showed down-regulation of neuro-protective/antiinflammatory DHCR24.These results suggest that Ab42 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 Ab release for clearance from neural cells.
Alzheimer’s disease;;Insulin resistance;;Ab peptides;;Insulin signaling;;Cholesterol synthesis pathway;;Pro-inflammatory response
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