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

Conrad N Trumbore, Aditya Raghunandan

Producción científica: Articlerevisión exhaustiva

2 Citas (Scopus)

Resumen

This paper suggests a chemical mechanism for the earliest stages of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) flow stresses provide the energy needed to induce molecular conformation changes leading to AD by initiating amyloid-β (Aβ) and tau aggregation. Shear and extensional flow stresses initiate aggregation in the laboratory and in natural biophysical processes. Energy-rich CSF flow regions are mainly found in lower brain regions. MRI studies reveal flow stress "hot spots" in basal cisterns and brain ventricles that have chaotic flow properties that can distort molecules such as Aβ and tau trapped in these regions into unusual conformations. Such fluid disturbance is surrounded by tissue deformation. There is strong mapping overlap between the locations of these hot spots and of early-stage AD pathology. Our mechanism creates pure and mixed protein dimers, followed by tissue surface adsorption, and long-term tissue agitation ultimately inducing chemical reactions forming more stable, toxic oligomer seeds that initiate AD. It is proposed that different flow stress energies and flow types in different basal brain regions produce different neurotoxic aggregates. Proliferating artery hardening is responsible for enhanced heart systolic pulses that drive energetic CSF pulses, whose critical maximum systolic pulse energy location migrates further from the heart with increasing vascular disease. Two glymphatic systems, carotid and basilar, are suggested to contain the earliest Aβ and tau AD disease pathologies. A key to the proposed AD mechanism is a comparison of early chronic traumatic encephalopathy and AD pathologies. Experiments that test the proposed mechanism are needed.

Idioma originalEnglish (US)
Páginas (desde-hasta)33-59
Número de páginas27
PublicaciónJournal of Alzheimer's Disease
Volumen90
N.º1
DOI
EstadoPublished - 2022

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