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?

Abstract

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.

An Alzheimer’s Disease Mechanism Based on Early Pathology, Anatomy, Vascular-Induced Flow, and Migration of Maximum Flow Stress Energy Location with Increasing Vascular Disease

“…[18] and expanded [5] based on the report of chaotic motions of the CSF within certain regions of the brain, especially in basal regions [3]. In this paper, this new approach is expanded to include anatomical correlations between A␤/tau pathology and regions shear in perivascular flow paths in the brain vascular system.…”

“…Whether or not there are chemical reactions relating to these conformational perturbations will depend on their energy as well as opportunities for reactions of the excited tau or A␤ molecules with their surroundings such as other stretched molecules or nearby membrane surfaces [71]. Figure 3 Putting all these facts together, it has been suggested that flow-induced stresses within the lower brain and cistern regions may be responsible for the initiation of A␤ and tau aggregation-and subsequent AD disease [5]. In this light, the decadal timing of this disease is of great interest.…”

“…We then demonstrate strong correlations among these hot spots and sites of early Aβ and tau pathology. The cerebral aqueduct region is suggested as one of the prime brain locations for the development of extensional fluid stress in tau protein [ 5 ].…”

“…A radically different approach that still maintains Aβ and tau as major components and is based on the effects of brain fluid motion has been suggested [ 18 ] and expanded [ 5 ] based on the report of chaotic motions of the CSF within certain regions of the brain, especially in basal regions [ 3 ]. In this paper, this new approach is expanded to include anatomical correlations between Aβ/tau pathology and regions of energetic CSF motion observable by MRI.…”

“…Previous papers have described the types of flow stress-induced conformation changes predicted for aggregation to proceed in the human brain [ 5, 18, 43 ]. Each of these changes is dependent on the amount of mechanical energy transferred to and converted into potential energy in each molecule.…”