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The same γ‐secretase accounts for the multiple intramembrane cleavages of APP
Author(s) -
Zhao Guojun,
Tan Jianxin,
Mao Guozhang,
Cui MeiZhen,
Xu Xuemin
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04302.x
Subject(s) - chemistry , gamma secretase , presenilin , amyloid precursor protein , cleavage (geology) , amyloid precursor protein secretase , peptide , microbiology and biotechnology , biochemistry , pharmacology , medicine , biology , alzheimer's disease , fracture (geology) , paleontology , disease
It has been hypothesized that different C‐terminus of β‐amyloid peptide (Aβ) may be generated by different γ‐secretase activities. Recently, we have identified a new ζ‐cleavage site at Aβ46, leading to an important finding that the C‐terminus of Aβ is produced by a series of sequential cleavages. This finding prompted us to examine the effects of the known γ‐secretase inhibitors on different steps of the γ‐secretase‐mediated sequential cleavages and specifically their effects on the formation and turnover of the intermediate Aβ 46 . Our results demonstrate that some of the known inhibitors, such as L‐685,458 and III‐31C as well as inhibitors IV and V, inhibit the formation of secreted Aβ 40/42 by inhibiting the formation of the intermediate Aβ 46 . However, most of the other inhibitors show no inhibitory effect on the formation of the intermediate Aβ 46 , but rather inhibit the turnover of Aβ 46 , resulting in its accumulation. In addition, the non‐steroidal anti‐inflammatory drugs (NSAIDs) ibuprofen and sulindac sulfide have no effect on the formation and turnover of Aβ 46 , but rather modulate the ratio of secreted Aβ at a step after the formation of Aβ 40 and Aβ 42 . Thus, our data strongly suggest that the multi‐sequential intramembrane cleavages of amyloid precursor protein C (APP) are likely catalyzed by the same γ‐secretase.