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- W2014420120 abstract "Increased synthesis of self-aggregating amyloid beta (Aβ) peptides caused by abnormal processing of amyloid precursor protein (APP) is a hallmark of Alzheimer's disease (AD) pathogenesis. Aβ mediates it's effect by disrupting the integrity of cell membrane and interacting with plasma membrane channels. The soluble form of Aβ aggregates into calcium (Ca2+) - permeable pores in the membrane. Aβ pores promote uncontrolled increase in the cytoplasmic Ca2+ concentration by allowing Ca2+ influx to the cell, in addition to enhancing the activity of Ca2+- permeable channels on the plasma membrane and intracellular compartments. The Ca2+ influx through Aβ pores upsets the otherwise fine-tuned micrometer-sized elementary Ca2+ release events and whole-cell Ca2+ response. The disrupted Ca2+ signaling in turn has the potential to alter cell function in many ways.Here, we have used computational modeling in conjunction with TIRF microscopy to study the function of Aβ pores in AD cells. TIRF microscopy was used to image Ca2+ flux through thousands of Aβ pores in parallel at the millisecond scale and single channel resolution. The fluorescence time-series from individual pores was idealized by extending the Maximum Likelihood-based method developed for separating signal from baseline in noisy quantal data (Bruno et al. 2013, Biophys. J. 105:68). The idealized data was used to developed data-driven models for the kinetics of Aβ pore at different stages of it's life. In addition to providing deep insights into the kinetics of Aβ pore, this study demonstrates that the massive imaging data obtained from thousands of channels in parallel using TIRF microscopy can be utilized for single molecule modeling in the same manner as electrical patch-clamp data. Employing the optical patch-clamp data for Markov chain modeling has the added advantage of the experiments being done under physiological conditions." @default.
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- W2014420120 date "2014-01-01" @default.
- W2014420120 modified "2023-09-28" @default.
- W2014420120 title "Learning the Kinetics of Amyloid β Pore in Alzheimer's Disease Pathology" @default.
- W2014420120 doi "https://doi.org/10.1016/j.bpj.2013.11.3052" @default.
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