β-Amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes

Abstract

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, β-amyloid (Aβ), 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’ Aβ(1–40) and Aβ(1–42), and (2) to examine whether treatment of astrocytes with Aβ results in degraded fragments of ECM. Aβ 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, Aβ peptide induced both MMP-3 and plasminogen activator-like activity from astrocytes. When medium from Aβ-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, Aβ 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.