title: γ-secretase modulators and presenilin 1 mutants act differently on presenilin/γ-secretase function to cleave Aβ42 and Aβ43.
abstract: Deciphering the mechanism by which the relative Aβ42(43) to total Aβ ratio is regulated is central to understanding Alzheimer disease (AD) etiology; however, the mechanisms underlying changes in the Aβ42(43) ratio caused by familial mutations and γ-secretase modulators (GSMs) are unclear. Here, we show in vitro and in living cells that presenilin (PS)/γ-secretase cleaves Aβ42 into Aβ38, and Aβ43 into Aβ40 or Aβ38. Approximately 40% of Aβ38 is derived from Aβ43. Aβ42(43) cleavage is involved in the regulation of the Aβ42(43) ratio in living cells. GSMs increase the cleavage of PS/γ-secretase-bound Aβ42 (increase k(cat)) and slow its dissociation from the enzyme (decrease k(b)), whereas PS1 mutants and inverse GSMs show the opposite effects. Therefore, we suggest a concept to describe the Aβ42(43) production process and propose how GSMs act, and we suggest that a loss of PS/γ-secretase function to cleave Aβ42(43) may initiate AD and might represent a therapeutic target.
authors.affiliation: Neuropsychiatry and Neurochemistry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. mokochi@psy.med.osaka-u.ac.jp
authors.forename: Masayasu
authors.initials: M
authors.lastname: Okochi
authors.forename: Shinji
authors.initials: S
authors.lastname: Tagami
authors.forename: Kanta
authors.initials: K
authors.lastname: Yanagida
authors.forename: Mako
authors.initials: M
authors.lastname: Takami
authors.forename: Takashi S
authors.initials: TS
authors.lastname: Kodama
authors.forename: Kohji
authors.initials: K
authors.lastname: Mori
authors.forename: Taisuke
authors.initials: T
authors.lastname: Nakayama
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ihara
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002470:Cell Survival; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013379:Substrate Specificity
chemical_list: D016229:Amyloid beta-Peptides; D050505:Mutant Proteins; D010455:Peptides; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases