Jr. Backstrom et al., MATRIX METALLOPROTEINASE-9 (MMP-9) IS SYNTHESIZED IN NEURONS OF THE HUMAN HIPPOCAMPUS AND IS CAPABLE OF DEGRADING THE AMYLOID-BETA PEPTIDE-(1-40), The Journal of neuroscience, 16(24), 1996, pp. 7910-7919
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.