TRANSLATIONAL QUANTITATIVE SYSTEMS PHARMACOLOGY MODEL OF TAUOPATHIES

Abstract

Quantitative systems pharmacology modelling can be valuable tool for understanding such a multifaceted process as tau protein accumulation. For prediction of the results of tau targeted therapy we propose a mechanistic model describing such tauopathies as Alzheimer's disease (AD), and frontotemporal degeneration (FTD) in human and tau accumulation in preclinical tauopathy model, mice carrying P301S(L) tau mutation. The model describes tau production, tau-microtubules interaction, tau modification, aggregation and propagation through different brain compartments. Tau oligomers serve as the key intermediates for fibril growth and as mediators of tau pathology connectivity-driven propagation mediators from entorhinal cortex through limbic system to neocortex. The driver of londitudinal disease progression in AD model is the decrease of autophagic degradation of tau fibrils. For FTD case we use assumption about tau mutation influence on polymerization and microtubule binding confirmed by in vitro data. The human model versions were calibrated across published biochemical data for soluble, insoluble tau, CSF tau and PET (18F-AV-1451 SUVR) data. The mouse model was calibrated across biochemical data for soluble (RAB, RIPA soluble fractions), insoluble tau (FA soluble fraction) in several brain structures, interstitial fluid and CSF of mouse. Model satisfactorily describes consecutive appearance of insoluble tau in different regions corresponding to Braak stages of AD. FTD data verification revealed that tau propagation parameters differ from AD situation. Mouse model version satisfactorily describes reduction of soluble tau in brain and accumulation of insoluble tau in the mouse P301S(L). Tau pathology propagation and gradual appearance of polymerized tau starting from entorhinal cortex through the limbic system to neocortex is also predicted correctly and follows the experimentally observed trend. Data on immunotherapy by antibodies HJ8.5 in mouse are described satisfactorily only if significant (10 times) increase of insoluble tau degradation is assumed, while blocking tau propagation only does not allow for describing the mouse data. Analogous degradation activation in humans, would lead to complete disappearance of tau in AD, but cause moderate effect in FTD according to the model. The proposed QSP model could be considered as platform for investigation of therapeutic impact on tau pathology and translational analysis.