Increased production of matrix metalloproteinases in enriched astrocyte and mixed hippocampal cultures treated with beta-amyloid peptides.

Growing evidence supports the notion of a functional relationship between the presence of the beta-amyloid (A beta) peptide and the production of inflammatory mediators in and around neuritic plaques of Alzheimer's disease. Tissue remodeling enzymes that are critical in peripheral inflammatory responses are the matrix metalloproteinases (MMPs), enzymes produced by neurons and glia. Thus, it was of interest to determine whether A beta may alter the expression of MMPs in glial and neuronal cultures. It was demonstrated that A beta (1-40) is a potent stimulator of MMP-9 and MMP-2 activity in addition to inducing the expression of a lower molecular weight, unidentified gelatinase activity in mixed hippocampal and astrocyte cultures. Shorter fragments of A beta were less effective in stimulating the production of these enzymes. The lower molecular weight activity was observed only in response to A beta, and not after treatment with various cytokines. In addition, both cultures express MMP-3 (stromelysin-1) in response to A beta peptides. These results suggest that MMPs may play a role in the development or progression of neuritic plaques, i.e., abnormal neurite outgrowth.