1. γ-Secretase modulators do not induce Aβ-rebound and accumulation of β-C-terminal fragment.
- Author
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Li, Ting, Huang, Yunhong, Jin, Shiyi, Ye, Liang, Rong, Na, Yang, Xiujuan, Ding, Yu, Cheng, Ziqiang, Zhang, Jinqiang, Wan, Zehong, Harrison, David C., Hussain, Ishrut, Hall, Adrian, Lee, Daniel Hong Seng, Lau, Lit-Fui, and Matsuoka, Yasuji
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SECRETASE inhibitors ,ALZHEIMER'S disease ,GLYCOPROTEINS ,AMYLOID beta-protein precursor ,BASAL ganglia diseases - Abstract
J. Neurochem. (2012) 121, 277-286. Abstract γ-secretase inhibitors (GSIs) have been developed to reduce amyloid-β (Aβ) production for the treatment of Alzheimer's disease by inhibiting the cleavage of amyloid precursor protein (APP). However, cross-inhibitory activity on the processing of Notch can cause adverse reactions. To avoid these undesirable effects, γ-secretase modulators (GSMs) are being developed to selectively reduce toxic Aβ production without perturbing Notch signaling. As it is also known that GSIs can cause a paradoxical increase of plasma Aβ over the baseline after a transient reduction (known as Aβ-rebound), we asked if GSMs would cause a similar rebound and what the potential mechanism might be. Our studies were performed with one GSI (LY-450139) and two chemically distinct GSMs. Although LY-450139 caused Aβ-rebound as expected in rat plasma, the two GSMs did not. Inhibition of APP processing by LY-450139 induced an accumulation of γ-secretase substrates, α- and β-C-terminal fragments of APP, but neither GSM caused such an accumulation. In conclusion, we discover that GSMs, unlike GSIs, do not cause Aβ-rebound, possibly because of the lack of accumulation of β-C-terminal fragments. GSMs may be superior to GSIs in the treatment of Alzheimer's disease not only by sparing Notch signaling but also by avoiding Aβ-rebound. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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