Beta-amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes.
The senile and neuritic plaque neuropathology of Alzheimer's disease (AD) is accompanied by an inflammatory response that includes activated astrocytes and microglia. Activated mononuclear phagocytes and reactive astrocytes, in response to inflammatory cytokines, secrete a set of extracellular matrix (ECM)-degrading enzymes that include the matrix metalloproteinases (MMPs). The major peptide component of senile plaques of AD, beta-amyloid (Abeta), stimulates the production of several MMPs from cultured rat astrocytes and microglia. The purpose of this study was two-fold: (1) to compare the pattern of MMP induction in rat astrocytes on treatment with 'soluble' and 'fibrillar' Abeta(1-40) and Abeta(1-42), and (2) to examine whether treatment of astrocytes with Abeta results in degraded fragments of ECM. Abeta aggregation differentially affected the production of MMP-2 and MMP-9 in astrocyte cultures. Activation experiments with amino phenyl mercuric acetate suggested that the 52-54 kDa gelatin-degrading activity was an activated form of MMP-2. In addition, Abeta peptide induced both MMP-3 and plasminogen activator-like activity from astrocytes. When medium from Abeta-treated, astrocyte cultures was immunoblotted for fibronectin, several immunopositive, lower molecular weight bands were observed as compared to untreated conditioned medium, suggestive of the presence of an active fibronectin-degrading protease. Thus, Abeta induces the secretion of several matrix-degrading proteases and stimulates matrix degradation in rat astrocytes. Since matrix-degrading proteases are elevated in AD brain, these proteases may influence the stability of ECM or other MMP substrates and thus may play a role in the neurotrophic/neurotoxic events associated with AD.
Deb
Suman
S
Department of Pharmacology and Therapeutics, University of South Florida College of Medicine, Tampa 33612-4799, USA.
Wenjun Zhang
J
J
Gottschall
Paul E
PE
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D005109:Extracellular Matrix / Q000187:drug effects* / Q000201:enzymology; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D008666:Metalloendopeptidases