Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA.
J Alzheimers Dis. 2021;79(3):979-1002. doi: 10.3233/JAD-201025.
Amyloid-β (Aβ) and tau oligomers have been identified as neurotoxic agents responsible for causing Alzheimer's disease (AD). Clinical trials using Aβ and tau as targets have failed, giving rise to calls for new research approaches to combat AD. This paper provides such an approach. Most basic AD research has involved quiescent Aβ and tau solutions. However, studies involving laminar and extensional flow of proteins have demonstrated that mechanical agitation of proteins induces or accelerates protein aggregation. Recent MRI brain studies have revealed high energy, chaotic motion of cerebrospinal fluid (CSF) in lower brain and brainstem regions. These and studies showing CSF flow within the brain have shown that there are two energetic hot spots. These are within the third and fourth brain ventricles and in the neighborhood of the circle of Willis blood vessel region. These two regions are also the same locations as those of the earliest Aβ and tau AD pathology. In this paper, it is proposed that cardiac systolic pulse waves that emanate from the major brain arteries in the lower brain and brainstem regions and whose pulse waves drive CSF flows within the brain are responsible for initiating AD and possibly other amyloid diseases. It is further proposed that the triggering of these diseases comes about because of the strengthening of systolic pulses due to major artery hardening that generates intense CSF extensional flow stress. Such stress provides the activation energy needed to induce conformational changes of both Aβ and tau within the lower brain and brainstem region, producing unique neurotoxic oligomer molecule conformations that induce AD.
淀粉样蛋白-β（Aβ）和 tau 寡聚物已被确定为导致阿尔茨海默病（AD）的神经毒性物质。使用 Aβ和 tau 作为靶点的临床试验已经失败，这就需要新的研究方法来对抗 AD。本文提供了这样一种方法。大多数基本的 AD 研究都涉及静止的 Aβ和 tau 溶液。然而，涉及蛋白质层流和拉伸流的研究表明，蛋白质的机械搅拌会诱导或加速蛋白质聚集。最近的 MRI 大脑研究揭示了大脑下区和脑干区域脑脊液（CSF）的高能量、混沌运动。这些研究以及显示 CSF 在大脑内流动的研究表明，有两个能量热点。这两个热点位于第三和第四脑室以及 Willis 血管区域附近。这两个区域也是最早的 Aβ和 tau AD 病理发生的位置。在本文中，提出了源自大脑下部和脑干区域主要大脑动脉的心脏收缩脉搏波，并通过这些脉搏波驱动大脑内的 CSF 流动，是引发 AD 甚至可能是其他淀粉样疾病的原因。进一步提出，这些疾病的触发是由于主要动脉硬化导致的收缩脉冲增强，从而产生强烈的 CSF 拉伸流动应力，这提供了引发 Aβ和 tau 在大脑下部和脑干区域发生构象变化所需的激活能，产生独特的神经毒性寡聚物分子构象，从而导致 AD。
