Clarification of pathogenic mechanism of Alzheimer disease
Under the leadership of OKOCHI Masayasu , Lecturer, Psychiatric Medicine, Course of Integrated Medicine, Graduate School of Medicine, Osaka University, a group of researchers have clarified the mechanism of amyloid ß42 that is thought to be a disease agent of Alzheimer disease.
In the brain of patients with Alzheimer disease, Amyloid-ß42 protein is accumulated and the accumulation of Amyloid-ß42 has been thought to be one of the causes of the disease. According to a traditional view, Amyloid-ß42 was one of the final products produced by enzyme γ-secretase. This group has discovered that γ-secretase itself was capable of decomposing Amyloid-ß42.
Amyloid-ß38 generated from decomposition is not a causative substance of Alzheimer disease. This group's achievements show that, in the successive decomposition, if Amyloid-ß42 is dissociated from the enzyme, it accumulates in the brain and causes Alzheimer disease, but if Amyloid-ß42 is not dissociated from the enzyme, it is detoxificated. This group's achievements will possibly promote the prevention of Alzheimer disease and/or the development of therapeutic drugs for it.
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 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.
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To learn more about this research, please read the full research report entitled " γ-Secretase Modulators and Presenilin 1 Mutants Act Differently on Presenilin/γ-Secretase Function to Cleave Aβ42 and Aβ43 " at this page of the Cell Reports website.
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