Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism
Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism
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DOI：
10.1021/bi992933h
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发表时间：
2000-05-30
期刊：
影响因子：
2.9
通讯作者：
Maggio, JE
中科院分区：
文献类型：
--
作者：
Esler, WP;Stimson, ER;Maggio, JE
由肽A β组成的淀粉样斑块是阿尔茨海默病（AD）发病机制的组成部分。我们通过监测AD脑组织或合成淀粉样蛋白原纤维中可溶性A β在淀粉样蛋白上的沉积来模拟淀粉样蛋白斑块生长的过程，并表明它是由两种不同的动力学过程介导的。在第一阶段，“对接”，A β加入淀粉样蛋白模板是完全可逆的（解离t（1/2）约为10分钟），而在第二阶段，“锁定”，沉积的肽以时间依赖性方式与模板不可逆地缔合（解离t（1/2）远大于1000分钟）。最近沉积的肽首先解离，而先前沉积的A β不可逆地“锁定”到模板上。因此，从单体到神经毒性淀粉样蛋白的转变是通过与模板的相互作用介导的，这也是朊病毒疾病的一种机制。有趣的是，两个A β肽轴承的主要序列改变涉及遗传性A β淀粉样变性表现出更快的锁相动力学比野生型A β。抑制沉积A β和模板之间的初始弱对接相互作用是一个可行的治疗目标，可以防止A β（（溶液））转化为A β（（淀粉样蛋白））中的关键构象转变，从而防止稳定的淀粉样蛋白积累。虽然热力学表明，抑制淀粉样蛋白组装将是困难的，本研究表明，蛋白质错误折叠疾病是动力学上容易受到干预。
Amyloid plaques composed of the peptide A beta are an integral part of Alzheimer's disease (AD) pathogenesis. We have modeled the process of amyloid plaque growth by monitoring the deposition of soluble A beta onto amyloid in AD brain tissue or synthetic amyloid fibrils and show that it is mediated by two distinct kinetic processes. In the first phase, "dock", A beta addition to the amyloid template is fully reversible (dissociation t(1/2) approximate to 10 min), while in the second phase, "lock", the deposited peptide becomes irreversibly associated (dissociation t(1/2) much greater than 1000 min) with the template in a time-dependent manner. The most recently deposited peptide dissociates first while A beta previously deposited becomes irreversibly "locked" onto the template. Thus, the transition from monomer to neurstoxic amyloid is mediated by interaction with the template, a mechanism that has also been proposed for the prion diseases. Interestingly, two A beta peptides bearing primary sequence alterations implicated in heritable A beta amyloidoses displayed faster lock-phase kinetics than wild-type A beta. Inhibiting the initial weak docking interaction between depositing A beta and the template is a viable therapeutic target to prevent the critical conformational transition in the conversion of A beta((solution)) to A beta((amyloid)) and thus prevent stable amyloid accumulation. While thermodynamics suggest that inhibiting amyloid assembly would be difficult, the present study illustrates that the protein misfolding diseases are kinetically vulnerable to intervention.