A multi-scale data-driven model of the Abeta pore function and Ca2+ toxicity in Alzheimer's disease

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Alzheimer's disease (AD) is a chronic neurodegenerative disorder that leads to progressive deterioration in a broad range of cognitive functions and finally death. Three amyloid beta (Aβ) peptides, Aβ40, Aβ42, and Aβ43 have been implicated as a key factors in the pathogenesis of AD. Recent findings indicate that extra- and intracellular accumulations of oligomeric forms of Aβ rather than large insoluble aggregates are the likely pathological culprits, and that their toxicity is mediated through uncontrolled elevation of cytosolic Ca2+ by formation of toxic Ca2+-permeable pores in the plasma membrane (PM). Yet, detailed information about the function of different Aβ pore types and which leaflet of the PM is more susceptible to pore formation are lacking. These pores have shown significant diversity and time dependent changes in their functional properties. Moreover, pharmacological comparisons between pores due to the three types of peptides are lacking. The highly heterogeneous and dynamic nature of Aβ pores poses extreme challenges in investigating their pathogenic mechanisms through traditional single channel approaches. Our goal is to fill a critical void in the understanding of Aβ-mediated Ca2+ signaling disruptions in AD using multi-scale data-driven modeling in conjunction with advanced imaging techniques having a resolution down to single channel level. Using our optical patch clamp technique, we will monitor and compare the gating properties and time- dependent evolution of hundreds of Aβ pores formed by extra- and intracellular Aβ oligomers. We will measure and compare the conductance properties, gating kinetics, and time-dependent evolution of the three Aβ pore types. We propose to perform parallel experiments on Aβ40, Aβ42, and Aβ43 pores in identical conditions to: (1) elucidate and compare their function in the presence of various modulators including Zinc, Aluminum, and Copper, (2) compare the effects of Aβ pore blockers such as NA7 and Bexarotene, (3) how natural phenols including Curcumin, Oleuropein, and Resveratrol affect their formation and evolution, and (4) how changes in membrane components including cholesterol and phosphatidylserine affect the function of Aβ pores. Driven progressively by experimental data, we will develop specific models for different variants (based on peak permeability) of each pore type, followed by combining these models into a unified model encompassing both the fast (milliseconds) gating kinetics and slow (tens of minutes and hours) evolution of each Aβ pore type. We will incorporate the effect of modulators and PM components into each model and test how the concurrent presence of different modulators affect Aβ pores' behavior in different cell membranes? We will use these models to perform long simulations (many hours or days) to better understand how pores evolve and how they contribute to overall Ca2+ toxicity as a function of time, spatial arrangement, motility, and ratio of Aβ40, Aβ42, and Aβ43 when inserted into PM and membranes of different intracellular organelles including ER, mitochondria, and lysosomes.