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• W2897789710 abstract "Recent imaging using specific tau PET tracers have suggested that tau pathology drives clinical outcome substantially more than amyloid accumulation. A significant challenge is to associate tau pathology to the firing activity of neuronal circuits of the specific brain regions that drive a given behavioral outcome. Human Induced pluripotent stem cell-derived neurons grown on in-vitro systems enabled with Multi-electrode arrays (MEAs) allow the study of electrophysiological properties of human neurons and enable the pharmacological and genetic studies of mechanism relevant to Tauopathies. We use Quantitative Systems Pharmacology, a mechanism-based advanced computer model of humanized neuronal circuits that has shown value in blindly predicting unexpected clinical outcomes in Alzheimer's disease and schizophrenia. This platform has previously been calibrated to an ADAS-Cog readout using historical clinical trials. Using publicly available data, we show how tau pathology in the somatodendritic compartment through a reduction of 15% of voltage-gated K+ channels, can affect the outcome of a more complex neuronal cortical network regarding BOLDfMRI readout and functional cognitive outcome. Interestingly only when applied to conditions of MCI, do we observe hyperexcitability that leads to lower cognitive performance (-10%) and can be almost completely reversed by the pharmacology of levetiracetam, albeit in an inverse U-shape dose-response. In other more typical AD cases, we observe a lower firing activity associated with a deficit in cognitive performance. In addition, we outline a strategy to use the MEAs technology to extrapolate the outcomes of action potential measures of hIPSC cells derived neurons measures with to the pathological neuronal circuit that is affected in tauopathies. Quantitative Systems Pharmacology is at the core of MAPTA a pre-competitive alliance funded and organized by Cohen Veterans Biosciences, a 501(c)3 nonprofit research organization aiming to accelerate the development of next-generation diagnostics and treatments for brain disorders. MAPTA is a powerful tool for better understanding the relationship of tau pathology to clinical symptoms." @default.
• W2897789710 created "2018-10-26" @default.
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• W2897789710 date "2018-07-01" @default.
• W2897789710 modified "2023-09-26" @default.
• W2897789710 title "O3‐01‐06: MAPTA (MODELING ALLIANCE FOR SYSTEMS PHARMACOLOGY IN TAUOPATHIES): MODELING THE IMPACT OF TAU ON HYPEREXCITABILITY IN MCI" @default.
• W2897789710 doi "https://doi.org/10.1016/j.jalz.2018.06.2775" @default.
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