Proteasome-mediated degradation of the C-terminus of the Alzheimer's disease β-amyloid protein precursor: effect of C-terminal truncation on the production of β-amyloid protein
Nunan, J and Williamson, NA and Hill, AF and Sernee, MF and Masters, CL and Small, DH, Proteasome-mediated degradation of the C-terminus of the Alzheimer's disease β-amyloid protein precursor: effect of C-terminal truncation on the production of β-amyloid protein, Journal of Neuroscience Research, 74, (3) pp. 378-385. ISSN 0360-4012 (2003) [Refereed Article]
The â-amyloid protein (Aâ) is derived by proteolytic processing of the amyloid protein precursor (APP). Cleavage of APP by â-secretase generates a C-terminal fragment (APP-CTFâ), which is subsequently cleaved by ã-secretase to produce Aâ. 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 Aâ production, APP-CTFâ and mutant forms of APP-CTFâ terminating on either side of the YENPTY sequence were expressed in CHO cells. Truncation of APP-CTFâ on the N-terminal side of the YENPTY sequence at residue 677 significantly decreased the amount of Aâ 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 ã-secretase processing, and consequently inhibits Aâ production. Therefore, the proteasome-dependent trafficking pathway of APP may be a valid therapeutic target for altering Aâ production in the Alzheimer's disease brain.