Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10

Biochemical, epidemiological, and genetic findings demonstrate a link betwe en cholesterol levels, processing of the amyloid precursor protein (APP), a nd Alzheimer's disease. In the present report, we identify the alpha -secre tase ADAM 10 (a disintegrin and metalloprotease) as a major target of the c holesterol effects on APP metabolism. Treatment of various peripheral and n eural cell lines with either the cholesterol-extracting agent methyl-beta - cyclodextrin or the hydroxymethyl glutaryl-CoA reductase inhibitor lovastat in resulted in a drastic increase of secreted alpha -secretase cleaved solu ble APP. This strong stimulatory effect was in the range obtained with phor bol esters and was further increased in cells overexpressing ADAM 10. In ce lls overexpressing APP, the increase of alpha -secretase activity resulted in a decreased secretion of AP peptides, Several mechanisms were elucidated as being the basis of enhanced alpha -secretase activity: increased membra ne fluidity and impaired internalization of APP were responsible for the ef fect observed with methyl-beta -cyclodextrin; treatment with lovastatin res ulted in higher expression of the alpha -secretase ADAM 10. Our results dem onstrate that cholesterol reduction promotes the nonamyloidogenic alpha -se cretase pathway and the formation of neuroprotective alpha -secretase cleav ed soluble APP by several mechanisms and suggest approaches to prevention o f or therapy for Alzheimer's disease.