γ-Secretase Modulators and Presenilin 1 Mutants Act Differently on Presenilin/γ-Secretase Function to Cleave Aβ42 and Aβ43
Masayasu Okochi,
Shinji Tagami,
Kanta Yanagida,
Mako Takami,
Takashi S. Kodama,
Kohji Mori,
Taisuke Nakayama,
Yasuo Ihara,
Masatoshi Takeda
Affiliations
Masayasu Okochi
Neuropsychiatry and Neurochemistry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Shinji Tagami
Neuropsychiatry and Neurochemistry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Kanta Yanagida
Neuropsychiatry and Neurochemistry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Mako Takami
Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kizugawa 619-0225, Japan
Takashi S. Kodama
Neuropsychiatry and Neurochemistry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Kohji Mori
Neuropsychiatry and Neurochemistry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Taisuke Nakayama
Neuropsychiatry and Neurochemistry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Yasuo Ihara
Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kizugawa 619-0225, Japan
Masatoshi Takeda
Neuropsychiatry and Neurochemistry, Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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 kcat) and slow its dissociation from the enzyme (decrease kb), 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.
