Matrix metalloproteinases as biomarkers of neurodegeneration

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DESCRIPTION (provided by applicant): Neurodegenerative disorders affect over 50 millions of Americans and cost annually over 500 billion dollars. Considerable efforts have been put forth to identifying biomarkers of neurodegeneration, that will allow for early and specific diagnosis of neurodenerative conditions that correlate longitudinally with the course of the disease (type 0); for evaluation of the effectiveness of neuroprotective intervention (type 1), or for predicting the clinical outcome (type 2, or surrogate endpoint). Matrix Metalloproteinases (MMPs) are the family of extracellular proteases that have been associated with many neurodegenerative disorders as modulators of demyelination, immune cell migration and blood-brain permeability. A series of recent reports have implicated MMPs as biomarkers of multiple sclerosis, stroke and Alzheimer's disease. Our own preliminary studies in the peripheral nervous system demonstrate that MMPs, particularly MMP-9, display critical attributes of a highly sensitive, specific and early biomarker of peripheral neurodegeneration. Using MMP-9 gene knockout model of Wallerain degeneration, and MMP-9-neutralizing therapy, we have established a direct link between MMP-9 levels and macrophage influx, myelin degradation and glial activation after peripheral nerve injury. These features of neurodegeneration will allow us to comparatively assess the value of MMP-9 and other MMPs as biomarkers of peripheral (sciatic nerve and L5 spinal nerve) and central (L5 spinal cord) neurodegeneration in rat. The utility of MMPs as surrogate biomarkers for spinal cord injury will be evaluated using experimental neuroprotective therapy with agents of different drug classes (i.e. riluzole, dizocilpine, minocycline). The overall goal of this proposal is to systematically evaluate the value of MMPs as biomarkers of central and/or peripheral neurodegeneration potentially useful for diagnostic, preclinical or clinical assessments in neurodegenerative conditions. Matrix Metalloproteainses (MMPs) is a protease family that controls degradation of structural molecules, such as collagens, cell surface receptor, cell adhesion molecules and other proteins of the extracellular spaces. Our studies demonstrate the important role of MMPs in peripheral neurodegeneration, immune cell recruitment and neuropathic pain. MMP-9 displays a particularly important feature: its activity is specific to degenerative conditions and its robust and early increase is readily quantifiable in tissues and body fluids, before any visible manifestation of injury. This proposal aims to determine the value of MMPs as biomarkers of neurodegeneration that could be used for the early diagnosis of neurodegenerative disease and the efficacy of neuroprotective therapy to spinal cord injury.