From reaction kinetics to dementia: A simple dimer model of Alzheimer ’s disease etiology

by Michael R. Lindstrom, Manuel B. Chavez, Elijah A. Gross-Sable, Eric Y. Hayden, David B. Teplow Oligomers of the amyloidβ-protein (Aβ) have been implicated in the pathogenesis of Alzheimer ’s disease (AD) through their toxicity towards neurons. Understanding the process of oligomerization may contribute to the development of therapeutic agents, but this has been difficult due to the complexity of oligomerization and the metastability of the oligomers thus formed. To understand the k inetics of oligomer formation, and how that relates to the progression of AD, we developed models of the oligomerization process. Here, we use experimental data from cell viability assays and proxies for rate constants involved in monomer-dimer-trimer kinetics to develop a simple mathematical model linking Aβ assembly to oligomer-induced neuronal degeneration. This model recapitulates the rapid growth of disease incidence with age. It does so through incorporation of age-dependent changes in rates of Aβ monomer production and elimination. The model also describes clinical progression in genetic forms of AD (e.g., Down ’s syndrome), changes in hippocampal volume, AD risk after traumatic brain injury, and spatial spreading of the disease due to foci in which Aβ production is elevated. Continued incorporation of clinical and basic science data into the current model will make it an increasingly relevant model system for doing theoretical calculations that are not feasible in biological sy...
Source: PLoS Computational Biology - Category: Biology Authors: Source Type: research