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Shear-Induced Amyloid Aggregation in the Brain: V. Are Alzheimer’s and Other Amyloid Diseases Initiated in the Lower Brain and Brainstem by Cerebrospinal Fluid Flow Stresses?
Journal of Alzheimer’s Disease ( IF 4 ) Pub Date : 2020-12-26 , DOI: 10.3233/jad-201025
Conrad N Trumbore 1
Affiliation  

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.

中文翻译:

大脑中剪切诱导的淀粉样蛋白聚集:V. 阿尔茨海默氏症和其他淀粉样蛋白疾病是否由脑脊液流动应力在下脑和脑干中引发?

淀粉样蛋白-β (Aβ) 和 tau 寡聚体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失败了,这引发了对抗击 AD 的新研究方法的呼吁。本文提供了这样一种方法。大多数基础的 AD 研究都涉及静止的 Aβ 和 tau 解决方案。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 脑部研究揭示了脑下部和脑干区域中脑脊液 (CSF) 的高能量、混乱运动。这些和显示脑内脑脊液流动的研究表明,有两个充满活力的热点。它们位于第三和第四脑室内以及威利斯血管区域附近。这两个区域也与最早的 Aβ 和 tau AD 病理的位置相同。在本文中,提出了从下脑和脑干区域的主要脑动脉发出的心脏收缩脉搏波,其脉搏波驱动大脑内的 CSF 流动,是引发 AD 和可能的其他淀粉样蛋白疾病的原因。进一步提出,这些疾病的触发是由于大动脉硬化引起的收缩脉冲加强,产生强烈的脑脊液伸展流动应力。这种压力提供了诱导下脑和脑干区域内 Aβ 和 tau 构象变化所需的激活能量,
更新日期:2020-12-29
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