MATRIX METALLOPROTEINASE-9 (MMP-9) IS SYNTHESIZED IN NEURONS OF THE HUMAN HIPPOCAMPUS AND IS CAPABLE OF DEGRADING THE AMYLOID-BETA PEPTIDE-(1-40)

We reported earlier that the levels of Ca2+-dependent metalloproteinas es are increased in Alzheimer's disease (AD) specimens, relative to co ntrol specimens. Here we show that these enzymes are forms of the matr ix metalloproteinase MMP-9 (EC 3.4.24.35) and are expressed in the hum an hippocampus. Affinity-purified antibodies to MMP-9 labeled pyramida l neurons, but not granular neurons or glial cells. MMP-9 mRNA is expr essed in pyramidal neurons, as determined with digoxigenin-labeled MMP -9 riboprobes, and the presence of this mRNA is confirmed with reverse transcriptase PCR. The cellular distribution of MMP-9 is altered in A D because 76% of the total 100 kDa enzyme activity is found in the sol uble fraction of control specimens, whereas only 51% is detectable in the same fraction from AD specimens. The accumulated 100 kDa enzyme fr om AD brain is latent and can be converted to an active form with amin ophenylmercuric acetate. MMP-9 also is detected in close proximity to extracellular amyloid plaques. Because a major constituent of plaques is the 4 kDa beta-amyloid peptide, synthetic A beta(1-40) was incubate d with activated MMP-9, The enzyme cleaves the peptide at several site s, predominantly at Leu(34)-Met(35) within the membrane-spanning domai n, These results establish that neurons have the capacity to synthesiz e MMP-9, which, on activation, may degrade extracellular substrates su ch as beta-amyloid. Because the latent form of MMP-9 accumulates in AD brain, it is hypothesized that the lack of enzyme activation contribu tes to the accumulation of insoluble beta-amyloid peptides in plaques.