Analyzing and modeling the kinetics of amyloid beta pores associated with Alzheimer’s disease pathology

Journal Article · Tue Sep 08 00:00:00 EDT 2015 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0137357· OSTI ID:1222472

Ullah, Ghanim ^[1]; Demuro, Angelo ^[2]; Parker, Ian ^[2]; Pearson, John E. ^[3]; Xu, Shang -Zhong ^[4]

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1. Univ. of South Florida, Tampa, FL (United States)
2. Univ. of California Irvine, Irvine, CA (United States)
3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
4. Univ. of Hull (United Kingdom)

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. As a result, we demonstrate the up-regulation of gating of various Ca²⁺ release channels due to Aβ pores and show that the extent and spatial range of such up-regulation increases as Aβ pores with low open probability and Ca²⁺ permeability transition into those with high open probability and Ca²⁺ permeability.

• Research Organization: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
• Sponsoring Organization: USDOE
• Grant/Contract Number: AC52-06NA25396
• OSTI ID: 1222472
• Journal Information: PLoS ONE, Vol. 10, Issue 9; ISSN 1932-6203
• Publisher: Public Library of Science
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
permeability
oocytes
Markov models
oligomers
fluorescence imaging
membrane potential
Alzheimer disease
cell membranes