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

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.

Lipid lowering in patients 75 years and older

More than twenty years ago,knowledge about the importance of cholesterol absorption and the potential therapeutic effect of its inhibition led to the discovery and clinical application of the first and only cholesterol absorption inhibitor to date–ezetimibe.Since then,ezetimibe has become a well-recognized player in lipid-lowering therapy.Recent findings of IMPROVE-IT and EWTOPIA 75 imply that elderly patients over the age of 75 years in particular benefit from ezetimibe.This review summarizes the evidence,discusses the possible underlying pathophysiological mechanisms and calls for a change in future dyslipidemia guidelines.

Drug targets beyond HMG-CoA reductase:Why venture beyond the statins?

In this review,we aim to convey a brief,select history of the development of cholesterol-lowering therapies.We focus particularly on the highly successful statins as well as setbacks that should serve as cautionary tales.We go on to preview recent developments that may complement,if not one day replace,the statins.Our focus is on pharmacological interventions,particularly those targeting the cholesterol biosynthetic pathway.Also,we examine therapies under current investigation that target the assembly of atherogenic lipoproteins(via apolipoprotein B or microsomal triglyceride transfer protein),the stability of the low-density lipoprotein-receptor(via PCSK9,proprotein convertase subtilisin kexin 9),or are designed to increase high-density lipoprotein-cholesterol(via inhibition of cholesteryl ester transfer protein).