title: Small-molecule inducers of Aβ-42 peptide production share a common mechanism of action.
abstract: The pathways leading specifically to the toxic Aβ42 peptide production, a key event in Alzheimer's disease (AD), are unknown. While searching for pathways that mediate pathological increases of Aβ42, we identified Aftin-4, a new compound that selectively and potently increases Aβ42 compared to DMSO (N2a cells: 7-fold; primary neurons: 4-fold; brain lysates: 2-fold) with an EC(50) of 30 μM. These results were confirmed by ELISA and IP-WB. Using affinity chromatography and mass spectrometry, we identified 3 proteins (VDAC1, prohibitin, and mitofilin) relevant to AD that interact with Aftin-4, but not with a structurally similar but inactive molecule. Electron microscopy studies demonstrated that Aftin-4 induces a reversible mitochondrial phenotype reminiscent of the one observed in AD brains. Sucrose gradient fractionation showed that Aftin-4 perturbs the subcellular localization of γ-secretase components and could, therefore, modify γ-secretase specificity by locally altering its membrane environment. Remarkably, Aftin-4 shares all these properties with two other "AD accelerator" compounds. In summary, treatment with three Aβ42 raising agents induced similar biochemical alterations that lead to comparable cellular phenotypes in vitro, suggesting a common mechanism of action involving three structural cellular targets.
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Ave., New York, NY 10021, USA.
authors.forename: Karima
authors.initials: K
authors.lastname: Bettayeb
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wenjie
authors.initials: W
authors.lastname: Luo
authors.forename: Victor
authors.initials: V
authors.lastname: Bustos
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Marc
authors.initials: M
authors.lastname: Flajolet
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D011345:Fenofibrate / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009930:Organic Chemicals / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics; D000091402:Prohibitins; D011485:Protein Binding / Q000187:drug effects; D011687:Purines / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D000077546:Roscovitine; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C088548:IMMT protein, human; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D009930:Organic Chemicals; D010446:Peptide Fragments; D000091402:Prohibitins; D011687:Purines; D011720:Pyrazoles; D012097:Repressor Proteins; D013449:Sulfonamides; C579636:aftin-4; C075222:amyloid beta-protein (1-42); D000077546:Roscovitine; D050995:Voltage-Dependent Anion Channel 1; D053829:Amyloid Precursor Protein Secretases; D000225:Adenine; D000068579:Celecoxib; D011345:Fenofibrate