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• W2094247263 abstract "The deposition of amyloid-β peptides (Aβ) in senile plaques (SPs) is a central pathological feature of Alzheimer's disease (AD). Since SPs are composed predominantly of Aβ1−42, which is more amyloidogenic in vitro, the enzymes involved in generating Aβ1−42 may be particularly important to the pathogenesis of AD. In contrast to Aβ1−40, which is generated in the trans-Golgi network and other cytoplasmic organelles, intracellular Aβ1−42 is produced in the endoplasmic reticulum/intermediate compartment (ER/IC), where it accumulates in a stable insoluble pool. Since this pool of insoluble Aβ1−42 may play a critical role in AD amyloidogenesis, we sought to determine how the production of intracellular Aβ is regulated. Surprisingly, the production of insoluble intracellular Aβ1−42 was increased by a putative γ-secretase inhibitor as well as by an inhibitor of the proteasome. We further demonstrate that this increased generation of Aβ1−42 in the ER/IC is due to a reduction in the turnover of Aβ-containing APP C-terminal fragments. We conclude that the proteasome is a novel site for degradation of ER/IC-generated APP fragments. Proteasome inhibitors may augment the availability of APP C-terminal fragments for γ-secretase cleavage and thereby increase production of Aβ1−42 in the ER/IC. Based on the organelle-specific differences in the generation of Aβ by γ-secretase, we conclude that intracellular ER/IC-generated Aβ1−42 and secreted Aβ1−40 are produced by different γ-secretases. Further, the fact that a putative γ-secretase inhibitor had opposite effects on the production of secreted and intracellular Aβ may have important implications for AD drug design." @default.
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• W2094247263 date "1999-12-30" @default.
• W2094247263 modified "2023-10-06" @default.
• W2094247263 title "A Distinct ER/IC γ-Secretase Competes with the Proteasome for Cleavage of APP" @default.
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• W2094247263 doi "https://doi.org/10.1021/bi991728z" @default.
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