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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

Citation

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]

DOI: doi:10.1002/jnr.10646

Abstract

The -amyloid protein (A) is derived by proteolytic processing of the amyloid protein precursor (APP). Cleavage of APP by -secretase generates a C-terminal fragment (APP-CTF), which is subsequently cleaved by -secretase to produce A. 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 A production, APP-CTF and mutant forms of APP-CTF terminating on either side of the YENPTY sequence were expressed in CHO cells. Truncation of APP-CTF on the N-terminal side of the YENPTY sequence at residue 677 significantly decreased the amount of A 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 -secretase processing, and consequently inhibits A production. Therefore, the proteasome-dependent trafficking pathway of APP may be a valid therapeutic target for altering A production in the Alzheimer's disease brain.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurosciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Neurodegenerative Disorders Related to Ageing
Author:Small, DH (Professor David Small)
ID Code:63310
Year Published:2003
Web of Science® Times Cited:48
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-04-28
Last Modified:2010-09-16
Downloads:0

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