MMP-7 and SNARE Cleavage in Neuroinflammation

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DESCRIPTION (provided by applicant): A variety of inflammatory conditions induce tissue damage through excess proteolysis. However, the extent to which proteolysis of neuronal substrates can contribute to brain pathology is less well understood. A particularly important family of proteolytic enzymes is the matrix metalloproteinases (MMPs), zinc- dependent, secreted endopeptidases that can cleave extracellular matrix proteins as well as cytokines and cell surface receptors. MMPs are produced within the brain and their production may be increased by pro-inflammatory cytokines and 2-amyloid. Moreover, elevated expression of MMPs has been reported in Alzheimer's disease, vascular dementia, and HIV-associated dementia. While some studies have examined the possibility that MMPs are neurotoxic, a full understanding of how elevated levels of these enzymes may influence neuronal physiology is lacking. Of particular importance is the potential for MMPs to influence neuronal networks via an effect on the synapse. Preliminary data shows that at least one MMP, MMP-7 inhibits synaptic vesicle release in vitro. Such data also shows that immunoreactivity for select SNARE protein, known to play a role in synaptic vesicle release, is reduced by exogenous MMP-7. The central hypothesis of the present proposal is that MMP-7 alters synaptic vesicle release via direct intrasynaptic cleavage of SNARE protein(s). The possibility that MMP-7 enters neurons via endocytosis and then mediates intrasynaptic cleavage of essential SNARE protein(s) will be examined. The rationale for the research is that if MMP-7 has direct effects on synaptic structure and function, it may contribute to synaptic dysfunction in the setting of CNS inflammation, and excess proteolysis may be considered as a target for neuroprotective therapeutics. The purpose of the application is to understand how MMP-7, a protease whose levels are increased in the brain inflammations, influences neuron to neuron communication. The relevance of this research to Public Health is that it may explain how inflammation contributes to neurological dysfunction. Excess levels of select proteases may be considered as novel targets for neuro-protective drugs.