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Proteolytic Processing of Alzheimers-Disease Beta-A4 Amyloid Precursor Protein in Human Platelets

Citation

Li, QX and Evin, G and Small, DH and Multhaup, G and Beyreuther, K and Masters, CL, Proteolytic Processing of Alzheimers-Disease Beta-A4 Amyloid Precursor Protein in Human Platelets, Journal of Biological Chemistry, 270, (23) pp. 14140-14147. ISSN 0021-9258 (1995) [Refereed Article]


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Copyright Statement

Copyright 1995 The American Society for Biochemistry and Molecular Biology, Inc.

Official URL: http://www.jbc.org/content/270/23/14140.abstract

DOI: doi:10.1074/jbc.270.23.14140

Abstract

The processing of amyloid precursor protein (APP) and production of βA4 amyloid are events likely to influence the development and progression of Alzheimer's disease, since βA4 is the major constituent of amyloid deposited in this disorder. Our previous studies showed that human platelets contain full-length APP (APP(FL)) and are a suitable substrate to study normal APP processing. In the present study, we show that a 22-kDa βA4-containing carboxyl-terminal fragment (22-CTF) of APP is present in unstimulated platelets. Both APP(FL) and 22-CTF are proteolytically degraded when platelets are activated with thrombin, collagen, or calcium ionophore A23187. Complete cleavage of APP(FL) and 22-CTF require the presence of extracellular calcium. Following stimulation in the presence of calcium, a new CTF of 17 kDa is generated, and the NH2-terminal epitope of βA4 amyloid is lost. Preincubation of platelets with the cell-permeable cysteine protease inhibitors calpeptin, (2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3- methylbutone ethyl ester (E64d), Na(α)-p-tosyl-L-lysine chloromethyl ketone, or calcium chelator EGTA before platelet stimulation inhibits the degradation of both APP(FL) and 22-CTF. Divalent metal ions including zinc, copper, and cobalt inhibit the degradation of APP(FL) and 22-CTF. This study suggests that a calcium-dependent neutral cysteine protease is involved in the proteolytic processing of an amyloidogenic species of APP in human platelets.

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:75428
Year Published:1995
Web of Science® Times Cited:85
Deposited By:Research Division
Deposited On:2012-01-30
Last Modified:2012-06-26
Downloads:0

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