A mechanistic model to predict effects of cathepsin B and cystatin C on β-amyloid aggregation and degradation
A mechanistic model to predict effects of cathepsin B and cystatin C on β-amyloid aggregation and degradation
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DOI：
10.1074/jbc.m117.811448
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发表时间：
2017-12-22
影响因子：
4.8
通讯作者：
Murphy, Regina M.
中科院分区：
文献类型：
--
作者：
Perlenfein, Tyler J.;Murphy, Regina M.
β-淀粉样蛋白（A β）聚集被认为引发阿尔茨海默病（AD）中神经变性事件的级联。目前正在努力开发降低A β浓度或抑制聚集的策略。组织蛋白酶B（CatB）将A β蛋白水解降解为非聚集片段，但被胱抑素C（CysC）有效抑制。已经表明，降低CysC将通过减轻CatB抑制来促进A β清除。然而，CysC结合A β并抑制A β聚集，这表明增加CysC的干预将阻止A β聚集。这两种方法已经在动物模型中进行了测试，产生了矛盾的结果，可能是因为CysC对A β降解与聚集的相反影响。在这里，我们试图开发一种模型，定量预测CysC和CatB对A β聚集的影响。测量在CatB或CysC不存在下的β聚集动力学。测定CatB降解A β的速率常数和CysC与A β结合的平衡常数。我们推导出一个数学模型，结合物料平衡和动力学速率方程。该模型准确地预测了不同CatB和CysC浓度下的A β聚集动力学。我们推导出降解和聚集的半衰期的近似表达式，并表明它们的比率可用于估计，在任何给定的A β，CatB，或CysC浓度，是否A β聚集或降解将导致。我们的研究结果可能是有用的设计实验和解释结果的调查操纵CysC浓度作为AD治疗。
beta-Amyloid (A beta) aggregation is thought to initiate a cascade of neurodegenerative events in Alzheimer's disease (AD). Much effort is underway to develop strategies to reduceA beta-concentration or inhibit aggregation. Cathepsin B (CatB) proteolytically degrades A beta into non-aggregating fragments but is potently inhibited by cystatin C (CysC). It has been suggested that decreasing CysC would facilitate A beta clearance by relieving CatB inhibition. However, CysC binds A beta and inhibits A beta aggregation, suggesting that an intervention that increases CysC would prevent A beta aggregation. Both approaches have been tested in animal models, yielding contradictory results, possibly because of the opposing influences of CysC on A beta degradation versus aggregation. Here, we sought to develop a model that quantitatively predicts the effects of CysC and CatB on A beta aggregation. A beta aggregation kinetics in the absence of CatB or CysC was measured. The rate constant for A beta degradation by CatB and the equilibrium constant for binding of CysC to A beta were determined. We derived a mathematical model that combines material balances and kinetic rate equations. The model accurately predicted A beta aggregation kinetics at various CatB and CysC concentrations. We derived approximate expressions for the half-times of degradation and aggregation and show that their ratio can be used to estimate, at any given A beta, CatB, or CysC concentration, whether A beta aggregation or degradation will result. Our results may be useful for designing experiments and interpreting results from investigations of manipulation of CysC concentration as an AD therapy.