Abstract
Neuroinflammation is an important factor in the pathogenesis of neurodegenerative diseases. Microglia-derived lysosomal cathepsins have been increasingly recognized as important inflammatory mediators that trigger signaling pathways that aggravate neuroinflammation. In vitro, a contribution to neuroinflammation processes has been shown for cathepsin X: however, the expression patterns and functional role of cathepsin X in neuroinflammatory brain pathology remain elusive. In this study we analyzed the expression, activity, regional distribution and cellular localization of cathepsin X in the rat brain with neuroinflammation-induced neurodegeneration. The unilateral injection of lipopolysaccharide (LPS) induced a strong upregulation of cathepsin X expression and its activity in the ipsilateral striatum. In addition to the striatum, cathepsin X overexpression was detected in other brain areas such as the cerebral cortex, corpus callosum, subventricular zone and external globus pallidus, whereas the upregulation was mainly restricted to activated microglia and reactive astrocytes. Continuous administration of the cathepsin X inhibitor AMS36 indicated protective effects against LPS-induced striatal degeneration, as seen by the attenuated LPS-mediated dilation of the lateral ventricles and partial decreased extent of striatal lesion. Taken together, our results indicate that cathepsin X plays a role as a pathogenic factor in neuroinflammation-induced neurodegeneration and represents a potential therapeutic target for neurodegenerative diseases associated with neuroinflammation.
Highlights
Neuroinflammation is associated with many neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington disease, amyotrophic lateral sclerosis and multiple sclerosis
We described for the first time that cathepsin X expression and its activity are strongly upregulated in vivo, i.e., in the rat brain striatum after LPSinduced lesion
Cathepsin X overexpression was found in the cerebral cortex, corpus callosum, subventricular zone and external globus pallidus, and in all of these regions, the upregulation was restricted to glial cells
Summary
Neuroinflammation is associated with many neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington disease, amyotrophic lateral sclerosis and multiple sclerosis. Accumulating evidence suggests that chronic innate neuroinflammation mediated by microglia and astrocytes is implicated in the progressive nature of these neurodegenerative disorders. Misfolded and aggregated proteins bind to pattern recognition receptors on glia cells and trigger an innate immune response, characterized by the release of inflammatory mediators, which contribute to the pathogenesis of AD. Some studies have shown beneficial and promising effects of anti-inflammatory agents, mixed results and inconsistencies between the preclinical and clinical studies require a better understanding of neuroinflammatory processes in neurodegenerative diseases (Schwartz and Shechter, 2010; Wang et al, 2015)
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