Kinetic Model With Feedback Cycle for Age-Dependent Beta Amyloid Accumulation in Mice

Abstract

Amyloid beta (Aβ) is believed to play a key role in Alzheimer's disease (AD), whose causes, progression, diagnosis, and treatment nonetheless remain poorly understood despite decades of research. Recent studies suggest that Aβ in its various forms participates in multiple mutual feedback loops ("vicious cycles") including tauopathy, oxidative stress, inflammation, calcium dysregulation, excitotoxicity, and probably many others, eventually leading to neurodegeneration and cognitive decline. Here, we explore a simple kinetic model of a coupled feedback vicious cycle for Aβ buildup based on literature data for Tg2576 mice. The model is used to examine the efficacy of various hypothetical therapeutic approaches, either singly or in combination, to mitigate Aβ buildup. While our computational results support the possible efficacy of combination interventions, they also suggest caution, inasmuch as clear synergy is not found. This kinetic approach highlights the essential importance of a vicious cycle of positive feedbacks in a quantitative model.