title: Lovastatin inhibits amyloid precursor protein (APP) beta-cleavage through reduction of APP distribution in Lubrol WX extractable low density lipid rafts.
abstract: Previous studies have described that statins (inhibitors of cholesterol and isoprenoid biosynthesis) inhibit the output of amyloid-beta (Abeta) in the animal model and thus decrease risk of Alzheimer's disease. However, their action mechanism(s) in Abeta precursor protein (APP) processing and Abeta generation is not fully understood. In this study, we report that lovastatin treatment reduced Abeta output in cultured hippocampal neurons as a result of reduced APP levels and beta-secretase activities in low density Lubrol WX (non-ionic detergent) extractable lipid rafts (LDLR). Rather than altering cholesterol levels in lipid raft fractions and thus disrupting lipid raft structure, lovastatin decreased Abeta generation through down-regulating geranylgeranyl-pyrophosphate dependent endocytosis pathway. The inhibition of APP endocytosis by treatment with lovastatin and reduction of APP levels in LDLR fractions by treatment with phenylarsine oxide (a general endocytosis inhibitor) support the involvement of APP endocytosis in APP distribution in LDLR fractions and subsequent APP beta-cleavage. Moreover, lovastatin-mediated down-regulation of endocytosis regulators, such as early endosomal antigen 1, dynamin-1, and phosphatidylinositol 3-kinase activity, indicates that lovastatin modulates APP endocytosis possibly through its pleiotropic effects on endocytic regulators. Collectively, these data report that lovastatin mediates inhibition of LDLR distribution and beta-cleavage of APP in a geranylgeranyl-pyrophosphate and endocytosis-dependent manner.
authors.affiliation: Department of Pathology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Je-Seong
authors.initials: JS
authors.lastname: Won
authors.forename: Yeong-Bin
authors.initials: YB
authors.lastname: Im
authors.forename: Mushfiquddin
authors.initials: M
authors.lastname: Khan
authors.forename: Miguel
authors.initials: M
authors.lastname: Contreras
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D008148:Lovastatin / Q000494:pharmacology*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016564:Amyloid beta-Protein Precursor; C017474:Lubrol WX; D011092:Polyethylene Glycols; D008148:Lovastatin