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O3‐01‐06: MAPTA (MODELING ALLIANCE FOR SYSTEMS PHARMACOLOGY IN TAUOPATHIES): MODELING THE IMPACT OF TAU ON HYPEREXCITABILITY IN MCI
Author(s) -
Geerts Hugo,
Spiros Athan,
Diaz Kristophe,
Lancashire Lee,
Jeromin Andreas,
Haas Magali
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.2775
Subject(s) - neuroscience , neurology , cognition , mechanism (biology) , psychology , medicine , physics , quantum mechanics
Background: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. Methods:We use Quantitative Systems Pharmacology, a mechanismbased 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. Results: Using publicly available data, we show how tau pathology in the somatodendritic compartment through a reduction of 15%of voltage-gatedK channels, can affect the outcome of amore complex neuronal cortical network regardingBOLDfMRI 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. Conclusions: 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.