Modeling the kinetics of amyloid beta pores and long-term evolution of their Ca2+ toxicity

Abstract

AbstractThe formation of cation-permeable pores due to amyloid beta (Aβ) in the plasma membrane (PM) and membranes of intracellular organelles has been shown to cause disruption of Ca2+ homeostasis in Alzheimer’s disease, leading to neuronal malfunction and degeneration. However, detailed information about the formation, function, and time-evolution of Aβ pores are still lacking. Here we present a comprehensive analysis to show that the Ca2+ toxicity of PM pores formed by Aβ42 progressively increases over the duration of the experiments that last for more than an hour. This mainly results from a progressively increasing number of pores and activity of individual pores having higher open probability (Po) and Ca2+ conductance. To gain deeper insight into the function and evolution of Aβ42 pores and establish their role in Ca2+ toxicity beyond experimental times scales, we developed a data-driven computational model that not only mimics the kinetics of these pores at a given time but also tracks their time-evolution over many hours. Our model suggests that the rising toxicity of Aβ42 pores over time is a combined result of the large number of short-lived pores with low Ca2+ conductance and long-lived higher-conductance pores but fewer in number. Analysis and modeling of the voltage-dependent data show that Aβ42 pores are most active when the cell’s membrane potential is near resting values, making the cell at rest especially more prone to Ca2+ disruptions.