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Volume 16, Number 24,
Issue of December 15, 1996
pp. 7910-7919
Copyright ©1996 Society for Neuroscience
Matrix Metalloproteinase-9 (MMP-9) Is Synthesized in Neurons of
the Human Hippocampus and Is Capable of Degrading the Amyloid-
Peptide (1-40)
Received Feb. 7, 1996; revised Sept. 3, 1996; accepted Oct. 4, 1996.
Jon R. Backstrom1,
Giselle P. Lim2,
Michael J. Cullen2, and
Zoltán A. Tökés1, 3
Departments of 1 Biochemistry and Molecular Biology and
2 Cell and Neurobiology, and the 3 USC/Norris
Comprehensive Cancer Center, School of Medicine, University of Southern
California, Los Angeles, California 90089
We reported earlier that the levels of Ca2+-dependent
metalloproteinases are increased in Alzheimer's disease (AD)
specimens, relative to control specimens. Here we show that these
enzymes are forms of the matrix metalloproteinase MMP-9 (EC3.4.24.35) and are expressed in the human hippocampus. Affinity-purified antibodies to MMP-9 labeled pyramidal neurons, but not granular neurons
or glial cells. MMP-9 mRNA is expressed 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 AD because 76% of the total 100 kDa enzyme activity is found in the soluble fraction of control
specimens, whereas only 51% is detectable in the same fraction from AD
specimens. The accumulated 100 kDa enzyme from AD brain is latent and
can be converted to an active form with aminophenylmercuric
acetate.
MMP-9 also is detected in close proximity to extracellular amyloid
plaques. Because a major constituent of plaques is the 4 kDa
 -amyloid peptide, synthetic A1-40 was incubated with
activated MMP-9. The enzyme cleaves the peptide at several sites,
predominantly at Leu34-Met35 within the
membrane-spanning domain. These results establish that neurons have the
capacity to synthesize MMP-9, which, on activation, may degrade
extracellular substrates such as -amyloid. Because the latent form
of MMP-9 accumulates in AD brain, it is hypothesized that the lack of
enzyme activation contributes to the accumulation of insoluble
-amyloid peptides in plaques.
Key words:
matrix metalloproteinases;
Alzheimer's
disease;
amyloid cleavage;
amyloid plaques;
gelatinase;
protease
activation
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