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- W2128195111 abstract "The β-amyloid protein (Aβ) is derived by proteolytic processing of the amyloid protein precursor (APP). Cleavage of APP by β-secretase generates a C-terminal fragment (APP-CTFβ), which is subsequently cleaved by γ-secretase to produce Aβ. Our previous studies have shown that the proteasome can cleave the C-terminal cytoplasmic domain of APP. To identify proteasome cleavage sites in APP, two peptides homologous to the C-terminus of APP were incubated with recombinant 20S proteasome. Cleavage of the peptides was monitored by reversed phase high-performance liquid chromatography and mass spectrometry. Proteasome cleaved the APP C-terminal peptides at several sites, including a region around the sequence YENPTY that interacts with several APP-binding proteins. To examine the effect of this cleavage on Aβ production, APP-CTFβ and mutant forms of APP-CTFβ terminating on either side of the YENPTY sequence were expressed in CHO cells. Truncation of APP-CTFβ on the N-terminal side of the YENPTY sequence at residue 677 significantly decreased the amount of Aβ produced, whereas truncation on the C-terminal side of residue 690 had little effect. The results suggest that proteasomal cleavage of the cytosolic domain of APP at the YENPTY sequence decreases γ-secretase processing, and consequently inhibits Aβ production. Therefore, the proteasome-dependent trafficking pathway of APP may be a valid therapeutic target for altering Aβ production in the Alzheimer's disease brain. © 2003 Wiley-Liss, Inc." @default.
- W2128195111 created "2016-06-24" @default.
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- W2128195111 date "2003-10-23" @default.
- W2128195111 modified "2023-10-16" @default.
- W2128195111 title "Proteasome-mediated degradation of the C-terminus of the Alzheimer's disease ?-amyloid protein precursor: Effect of C-terminal truncation on production of ?-amyloid protein" @default.
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- W2128195111 doi "https://doi.org/10.1002/jnr.10646" @default.
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