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• W2980482012 abstract "Recent studies suggest that tau pathology follows a well-defined trajectory in the human brain, but it is unclear how CSF dynamics or Tau PET imaging relate to the processes of secretion, uptake and axonal transport in human brain regions. In addition, there is increasing evidence that tau pathology might affect synaptic function before the appearance of tau aggregates. A Quantitative Systems Pharmacology (QSP) approach based on experimental biological data, can simulate the effect of tau antibodies on seed-competent tau spreading in a spatio-temporal model including competition with monomeric tau, secretion, diffusion, binding to HSPG and pinocytosis, and axonal transport. Similarly, the subtle effects of tau pathology on voltage-gated ion channels and neuronal activity can be modeled in ADAS-Cog calibrated neuronal networks. After introduction of the pharmacology and PK profile of tau antibodies and using experimentally determined concentrations of seed-competent tau in brain regions in different Braak stages, inhibition of tau uptake and its effect on axonal-transport mediated tau progression can be modeled. We will show examples of the effects of sensitivity (potency) versus selectivity of the anti-tau antibody and the impact on neuronal firing as a consequence of comedications and genotypes. Modeling the effect of tau pathology on specific Na+ and K+ channels in single neurons allows to generate hypotheses about preclinical observations in hIPSC cells with Multi-Electrode Array readout. Extrapolating these findings in a complete neuronal network can explain preclinical outcome in a combined APP-Tau Tg mouse model and clinical observations of hyperactivity in early stages. The platform based on biological principles suggest that the anti-tau antibody effect at the site of action could be different from the CSF dynamics, because of the different levels and processes involved, allowing to identify optimal doses, pharmacology and patient populations for each antibody. Using a neuronal circuit-based computer model, the effect of subtle tau-mediated changes on emergent properties more closely related to clinical outcomes can be predicted. MAPTA (Modeling Alliance for Systems Pharmacologies in Tauopathies) aims to support drug discovery and development in tauopathies by formalizing the knowledge about biological processes in a mathematical computer model." @default.
• W2980482012 created "2019-10-25" @default.
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• W2980482012 date "2019-07-01" @default.
• W2980482012 modified "2023-09-27" @default.
• W2980482012 title "P3-066: MECHANISTIC MODELING OF TAU PROPAGATION IN VIVO AND EFFECT ON ELECTROPHYSIOLOGY" @default.
• W2980482012 doi "https://doi.org/10.1016/j.jalz.2019.06.3093" @default.
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