Elevated levels of matrix metalloproteinases-9 and -1 and of tissue inhibitors of MMPs, TIMP-1 and TIMP-2 in postmortem brain tissue of progressive supranuclear palsy

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Abstract

We determined the levels and tissue localization of matrix metalloproteinases (MMPs) as well as their endogenous tissue inhibitors (TIMPs) in postmortem brain tissue from 13 patients with progressive supranuclear palsy (PSP) and 8 age-matched controls. MMP-9 expression was significantly increased in both the frontal cortex (p=0.002) and substantia nigra (p=0.003) of PSP cases as compared to controls whereas MMP-1 levels were increased in the substantia nigra (p=0.01) but unchanged in the frontal cortex (p=0.41). Levels of the endogenous tissue inhibitors of MMPs, TIMP-1 and TIMP-2 were significantly elevated in the substantia nigra (TIMP-1: p=0.004, TIMP-2: p=0.01). Levels of TIMPs were unchanged in PSP frontal cortex as compared to control cases. Together, these data show alterations of MMPs and TIMPs in the substantia nigra as well as in the frontal cortex of PSP, consistent with the possibility that alterations in MMPs/TIMPs may contribute to disease pathogenesis.

Introduction

Progressive supranuclear palsy is a rare neurodegenerative disorder, characterized by the appearance of supranuclear gaze palsy in addition to postural instability, dysarthria, truncal dystonia, parkinsonism and dementia. The hallmark pathology is the presence of straight neurofibrillary filaments and tau-positive tangles and extensive neuronal degeneration and gliosis in multiple nuclei located both within the basal ganglia, forebrain and brainstem [1], [2], [3].

The etiological basis of PSP is unknown; however, there is a growing body of evidence suggesting a contributory role of mitochondrial dysfunction and oxidative stress in the pathogenesis of PSP [4]. One consequence of increased oxidative stress may be the activation of matrix metalloproteases (MMPs). MMPs are a family of Zn2+-endopeptidases that are characterized by their ability to digest components of the extracellular matrix such as collagen, proteoglycan and laminin [5], [6]. MMPs in the brain are synthesized primarily by endothelial cells, astrocytes, microglia and neurons [7]. Previous reports have indicated that MMPs are involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) [8], [9], [10] and amyotrophic lateral sclerosis (ALS) [11], [12], and most recently Parkinson's disease (PD) [13].

Tight regulation of MMP expression occurs physiologically and the major endogenous counter-regulators of MMPs, the tissue inhibitors of the matrix metalloproteinases (TIMPs), are a family of at least four related proteins. In addition to their MMP-inhibitory function, TIMP-1 and TIMP-2 may act as growth factors [14], [15].

Based on the hypothesis that the generation of free radicals stimulates the expression/activity of MMPs and that free radical-mediated damage is a key mediator of neuronal damage in PSP, it is tempting to speculate that MMPs may be involved in the pathophysiology of PSP. In the present study, we measured the levels of MMP-2 and MMP-9 via zymography, levels of MMP-1 via western blot analysis, and localized the tissue distribution of MMP-2 and MMP-9 immunohistochemically in frontal cortical areas of PSP from pathologically confirmed cases of PSP and age-matched controls. We quantified the levels of TIMP-1 and TIMP-2 in PSP and control cases using ELISA.

Section snippets

Tissue specimens

Tissue from 13 cases with pathologically confirmed PSP (age=73.23±8.27 years, M/F=8:7, PMI=17.31±7.67 h, data are mean±standard deviation) and 8 control cases (age=74.38±8.14 years, M/F=5:3, PMI=16.50±4.31 h) was provided by the Harvard Brain Tissue Resource Center (Belmont, MA, USA). Cortical tissue was available from all cases; tissue from the substantia nigra was available from eight PSP and five control cases. There was no significant difference in age, PMI or gender between the PSP and

Levels of MMP-2, MMP-9 and MMP-1 as well as TIMP-1 and TIMP-2 in frontal cortex and substantia nigra

MMP-9 levels were significantly increased in the frontal cortex (p=0.002) and substantia nigra (p=0.003) from PSP cases as compared to cortical and nigral samples from age-matched control cases (Fig. 1). The band at 130 kDa is thought to be a complex of MMP and TIMP1. Nigral levels of MMP-1 were significantly elevated (p=0.01), but no differences were observed in the frontal cortex of PSP cases relative to control cases (Fig. 2). Cortical and nigral MMP-2 levels were not different between

Discussion

In the present study, we found increased MMP-1 activity in the substantia nigra of PSP cases as compared to controls as well as increased MMP-9 activity in PSP substantia nigra and frontal cortex. These data coupled with our results showing increased TIMP-1 and TIMP-2 levels in PSP substantia nigra lends credence to the hypothesis that an imbalance in expression/activity of MMPs and TIMPs may contribute to PSP pathophysiology.

Increased expression of MMPs have been reported in postmortem tissue

Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft (S.L) and the Society for Progressive Supranuclear Palsy (S.L. and D.S.A.), the Department of Defense, NIH, the ALS Association, the Huntington's Disease Society of America and the Hereditary Disease Foundation (M.F.B.).

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