Analyzing And Modeling The Kinetics Of Amyloid Beta Pores Associated With Alzheimer'S Disease Pathology

Amyloid beta (A beta) oligomers associated with Alzheimer's disease (AD) form Ca2+-permeable plasma membrane pores, leading to a disruption of the otherwise well-controlled intracellular calcium (Ca2+) homeostasis. The resultant up-regulation of intracellular Ca2+ concentration has detrimental implications for memory formation and cell survival. The gating kinetics and Ca2+ permeability of A beta pores are not well understood. We have used computational modeling in conjunction with the ability of optical patch-clamping for massively parallel imaging of Ca2+ flux through thousands of pores in the cell membrane of Xenopus oocytes to elucidate the kinetic properties of A beta pores. The fluorescence time-series data from individual pores were idealized and used to develop data-driven Markov chain models for the kinetics of the A beta pore at different stages of its evolution. Our study provides the first demonstration of developing Markov chain models for ion channel gating that are driven by optical-patch clamp data with the advantage of experiments being performed under close to physiological conditions. Towards the end, we demonstrate the upregulation of gating of various Ca2+ release channels due to A beta pores and show that the extent and spatial range of such up-regulation increases as A beta pores with low open probability and Ca2+ permeability transition into those with high open probability and Ca2+ permeability.