Quantitative systems pharmacology model of the effect of tau hyperphosphorylation on synaptic plasticity.

Abstract

The hyperphosphorylated tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease. Fyn-dependent tau hyperphosphorylation plays a major role in excitotoxicity of extrasynaptic NMDAr. Long-term potentiation (LTP) of excitatory synaptic transmission is a key mechanism for learning and memory. In animal models of Alzheimer's disease (AD), tau hyperphosphorylation reduces LTP. Tau phosphorylation level in the cell is balanced through phosphorylation by protein kinases and dephosphorylation by phosphates. Tau hyperphosphorylation has been implicated in glutamate excitotoxicity and calcium released from ER (endoplasmic reticulum), which leads to synaptic dysfunction. Tau pathology is modeled often okadaic acid (OA) inhibits the ability of PP2A to dephosphorylate tau. Increases of PP2A inhibitors have been reported in AD's patients. Quantitative systems pharmacology (QSP) model of synaptic plasticity was developed to investigate influence of tau hyperphosphorylation on impairment of LTP. The model describes a calcium influx in postsynapse through acetylcholine and glutamate receptors, calcium release from EPR, depending on IP3 receptors, activation of kinase/phosphatase cascade, tau phosphorylation and AMPA receptors phosphorylation level. Phosphorylation of AMPA receptors is associated with LTP. Influence of hyperphosphorylated tau on extrasynaptic NMDAr and calcium release from ER impairs the synaptic plasticity. Various data on synaptic plasticity in presence of different effectors (amyloid beta, memantine, SSR180711 etc.), available from the literature, are used for verification. The model qualitatively describes tau hyperphosphorylation, impairment of LTP by tau hyperphosphorylation influence and effect of tau antibody, kinase and phosphatase inhibitors. It demonstrates that: 1) tau with anti-aggregant properties may lead to a robust LTP, that was even more pronounced than control tau 2) antibody to tau decreases tau hyperhyperphosphorylation and restores LTP reduced by OA influence 3) inhibition of GSK-3b kinase leads attenuates hyperphosphorylation and leads to recovery of LTP CONCLUSION: The QSP model describes an influence of tau hyperphosphorylation on receptor's excitotoxicity and released calcium from ER (high activity of PP2b, increased intracellular calcium concentration). Our model allows to explore change of LTP under the influence of tau targeting therapy.