Pathogenic A beta induces the expression and activation of matrix metalloproteinase-2 in human cerebrovascular smooth muscle cells.

Abstract:

:Cerebral amyloid angiopathy (CAA) is a major pathological feature of Alzheimer's disease and related disorders. Human cerebrovascular smooth muscle (HCSM) cells, which are intimately associated with CAA, have been used as an in vitro model system to investigate pathologic interactions with amyloid beta protein (A beta). Previously we have shown that pathogenic forms of A beta induce several pathologic responses in HCSM cells including fibril assembly at the cell surface, increase in the levels of A beta precursor, and apoptotic cell death. Here we show that pathogenic A beta stimulates the expression and activation of matrix metalloproteinase-2 (MMP-2). Furthermore, we demonstrate that the increase in MMP-2 activation is largely caused by increased expression of membrane type-1 (MT1)-MMP expression, the primary MMP-2 activator. Finally, treatment with MMP-2 inhibitors resulted in increased HCSM cell viability in the presence of pathogenic A beta. Our findings suggest that increased expression and activation of MMP-2 may contribute to HCSM cell death in response to pathogenic A beta. In addition, these activities may also contribute to loss of vessel wall integrity in CAA resulting in hemorrhagic stroke. Therefore, further understanding into the role of MMPs in HCSM cell degeneration may facilitate designing therapeutic strategies to treat CAA found in AD and related disorders.

journal_name

J Neurochem

authors

Jung SS,Zhang W,Van Nostrand WE

doi

10.1046/j.1471-4159.2003.01745.x

keywords:

subject

Has Abstract

pub_date

2003-06-01 00:00:00

pages

1208-15

issue

5

eissn

0022-3042

issn

1471-4159

pii

1745

journal_volume

85

pub_type

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