Matrix Metalloproteinase-9 (MMP-9) is Synthesized in Neurons of the Human Hippocampus and is Capable of Degrading the Amyloid-ß Peptide (1-40)
This paper established several important points regarding matrix degrading enzymes. First, we established that MMP-9 is not restricted to the connective tissue but it may be found in certain neurons of the hippocampal region of the brain. MMP-9 was previously thought to be a collagen-degrading enzyme whose activity was limited to connective tissue and was particularly elevated in metastatic cancers. Second, in situ hybridization of riboprobes for the MMP-9 gene product confirmed that the MMP-9 was synthesized by neurons and not secondarily taken up by these cells. Third, the neurons that accumulated MMP-9 were neurons in the specific brain areas susceptible to neuronal death in Alzheimer’s disease. The amount of MMP-9 was greater in Alzheimer’s that control brain specimens, and the enzyme was latent. When artificially activated, MMP-9 was shown to degrade amyloid-ß peptide, the precursor to the plaque material found in Alzheimer’s disease.
From our observations, we hypothesized that accumulation of inactive MMP-9 contributes to the pathogenesis of Alzheimer’s disease. The normal brain substrate for MMP-9 is not known, although tachykinins contain cleavage sites for the enzyme; in fact, our studies indicate that MMP-9 degrades the tachykinin neurotransmitter substance P more rapidly that the putative degradation enzyme. This paper was significant in the area of Alzheimer’s research because it focused on the potential for neurons to control the composition of their extracellular matrix and it suggested an association between neurodegeneration and the abnormal processing and secretion of matrix-degrading enzymes.