Analyzing and Modeling the Kinetics of Amyloid Beta Pores Associated with Alzheimer's Disease Pathology

PloS One
Ghanim UllahJohn E Pearson

Abstract

Amyloid beta (Aβ) 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 Aβ 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 Aβ 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 Aβ 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 up-regulation of gating of various Ca2+ release channels due to Aβ pores and show that the extent and spat...Continue Reading

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Citations

Mar 24, 2016·Scientific Reports·Alba EspargaróRaimon Sabate
Jan 18, 2017·Genesis : the Journal of Genetics and Development·Amy K Sater, Sally A Moody
Apr 25, 2018·Journal of Alzheimer's Disease : JAD·Nelson Arispe, Antonio De Maio
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Mar 14, 2019·Frontiers in Physiology·Mardi J NenniAaron M Zorn
Dec 29, 2020·Genesis : the Journal of Genetics and Development·Cameron R T Exner, Helen Rankin Willsey
Sep 25, 2018·Cell Calcium·Patrick TogliaGhanim Ullah
Jul 5, 2018·Biophysical Journal·Syed Islamuddin ShahGhanim Ullah

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Methods Mentioned

BETA
fluorescence imaging

Software Mentioned

QUB
Meta
Morph
CellSpecks

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