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A novel metalloprotease in rat brain cleaves the amyloid precursor protein of Alzheimer's disease generating amyloidogenic fragments

Citation

Mok, SS and Evin, G and Li, QX and Smith, AI and Beyreuther, K and Masters, CL and Small, DH, A novel metalloprotease in rat brain cleaves the amyloid precursor protein of Alzheimer's disease generating amyloidogenic fragments, Biochemistry, 36, (1) pp. 156-163. ISSN 0006-2960 (1997) [Refereed Article]

Copyright Statement

Copyright 1997 American Chemical Society

DOI: doi:10.1021/bi961848w

Abstract

The amyloid protein (Aβ or βA4) is the major constituent of amyloid plaques in the Alzheimer's disease brain. Aβ is cleaved from the amyloid precursor protein (APP) by a mechanism which is poorly understood. Cell culture studies suggest that APP may be cleaved by secretases within the late Golgi compartment. Studies performed so far have mainly used exogenous APP and synthetic peptides as substrates. For this study, a Golgi and plasma membrane-enriched fraction was isolated from rat brain and incubated at 37 °C at pH 7.2 to study the degradation of endogenous APP. The breakdown of APP was accompanied by the concomitant generation of Aβ-containing C- terminal fragments, in a time-dependent fashion. The metal ion chelators EDTA and 1,10-phenanthroline inhibited this degradation. The inhibition by EDTA was reversed by 50 μM Zn2+ but not by other metal ions. The protease activity was not inhibited by cysteine, serine or aspartic protease inhibitors nor was it inhibited by compounds which are inhibitors of known metalloendopeptidases and matrix metalloproteinases (cFP, phosphoramidon and TIMP-2). Our data suggest that a novel Zn2+-dependent metalloprotease activity associated with a Golgi and plasma membrane-enriched fraction can degrade endogenous APP to generate Aβ containing C-terminal fragments. This protease may generate amyloidogenic fragments of APP which may serve as precursors for Aβ.

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:75419
Year Published:1997
Web of Science® Times Cited:17
Deposited By:Research Division
Deposited On:2012-01-30
Last Modified:2013-05-07
Downloads:0

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