The objective of this proposal is to test the hypothesis that the accumulation of characteristic proteinaceous deposits in Alzheimer-affected brain regions (ie. hippocampus) may be the result of aberrant regulation of proteinases. Our recent pilot study identified the three major neutral proteinases that are detectable in the human hippocampus, MP-130, MP-100, and MP-70. All are Ca-dependent metalloproteinases and are distinguishable from calpain. Since the distribution of two of these enzymes, MP-130 and MP-100, differs between control and Alzheimer specimens, we propose to investigate them in greater depth. The availability of these enzymes will be measured in hippocampal and cerebral hemisphere specimens, and their possible correlation with neuropathological parameters evaluated. The enzymes will be purified so that their cleavage specificity and in situ substrate preference, metal ion dependence, and possible activation or destruction by serine proteases can be established. Specific monoclonal antibodies will be raised against the purified enzymes and they will be used for the immunohistochemical localization of the enzymes, and for the testing of potential structural similarities between the brain-derived and other metalloproteinases derived from non-neuronal cell tissues. The subcellular distribution of these enzymes, as demonstrated with immunohistological techniques, and the application of special chromogenic peptide-substrates for the cytochemical localization of their activities in Alzheimer and control specimens will help to assess whether altered processing or compartmentalization is related to the pathogenesis of brain lesions.
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| Backstrom, J R; Lim, G P; Cullen, M J et al. (1996) Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1-40). J Neurosci 16:7910-9 |
| Lim, G P; Backstrom, J R; Cullen, M J et al. (1996) Matrix metalloproteinases in the neocortex and spinal cord of amyotrophic lateral sclerosis patients. J Neurochem 67:251-9 |
| Backstrom, J R; Tokes, Z A (1995) The 84-kDa form of human matrix metalloproteinase-9 degrades substance P and gelatin. J Neurochem 64:1312-8 |
