title: Statins cause intracellular accumulation of amyloid precursor protein, beta-secretase-cleaved fragments, and amyloid beta-peptide via an isoprenoid-dependent mechanism.
abstract: The use of statins, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that block the synthesis of mevalonate (and downstream products such as cholesterol and nonsterol isoprenoids), as a therapy for Alzheimer disease is currently the subject of intense debate. It has been reported that statins reduce the risk of developing the disorder, and a link between cholesterol and Alzheimer disease pathophysiology has been proposed. Moreover, experimental studies focusing on the cholesterol-dependent effects of statins have demonstrated a close association between cellular cholesterol levels and amyloid production. However, evidence suggests that statins are pleiotropic, and the potential cholesterol-independent effects of statins on amyloid precursor protein (APP) metabolism and amyloid beta-peptide (A beta) genesis are unknown. In this study, we developed a novel in vitro system that enabled the discrete analysis of cholesterol-dependent and -independent (i.e. isoprenoid-dependent) statin effects on APP cleavage and A beta formation. Given the recent interest in the role that intracellular A beta may play in Alzheimer disease, we analyzed statin effects on both secreted and cell-associated A beta. As reported previously, low cellular cholesterol levels favored the alpha-secretase pathway and decreased A beta secretion presumably within the endocytic pathway. In contrast, low isoprenoid levels resulted in the accumulation of APP, amyloidogenic fragments, and A beta likely within biosynthetic compartments. Importantly, low cholesterol and low isoprenoid levels appeared to have completely independent effects on APP metabolism and A beta formation. Although the implications of these effects for Alzheimer disease pathophysiology have yet to be investigated, to our knowledge, these results provide the first evidence that isoprenylation is involved in determining levels of intracellular A beta.
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA. s-cole4@northwestern.edu
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Cole
authors.forename: Aneta
authors.initials: A
authors.lastname: Grudzien
authors.forename: Ingrid O
authors.initials: IO
authors.lastname: Manhart
authors.forename: Brent L
authors.initials: BL
authors.lastname: Kelly
authors.forename: Holly
authors.initials: H
authors.lastname: Oakley
authors.forename: Robert
authors.initials: R
authors.lastname: Vassar
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001253:Astrocytes / Q000378:metabolism; D001692:Biological Transport; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D017368:Protein Prenylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013729:Terpenes / Q000737:chemistry* / Q000378:metabolism; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013729:Terpenes; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse