University Of Tasmania

File(s) under permanent embargo

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

journal contribution
posted on 2023-05-17, 10:03 authored by Mok, SS, Evin, G, Li, QX, Smith, AI, Beyreuther, K, Masters, CL, David SmallDavid Small
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.


Publication title









Menzies Institute for Medical Research


Amer Chemical Soc

Place of publication

1155 16Th St, Nw, Washington, USA, Dc, 20036

Rights statement

Copyright © 1997 American Chemical Society

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

Usage metrics