Cystatin C in aging and in Alzheimer’s disease

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• 作者：Paul M. Mathews^a ; ^c ; Efrat Levy^a ; ^b ; ^c ; ^{elevy@nki.rfmh.org}
• 关键词：Cystatin C ; Alzheimer&rsquo ; s disease ; Cerebral amyloidosis ; Amyloid ; Aβ ; Neurodegeneration
• 刊名：Ageing Research Reviews
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：32
• 期：Complete
• 页码：38-50
• 全文大小：1868 K
• 卷排序：32

文摘

Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer’s disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.