Description of amyloid beta influence on synaptic plasticity and tau hyperphosphorylation by mechanistic quantitative systems pharmacology model

Abstract

AbstractBackgroundLong‐term potentiation (LTP) is a dependent increase in synaptic plasticity that may be an appropriate experimental and theoretical model for learning and memory. In animal models of Alzheimer’s disease (AD), amyloid beta (Aβ) impacts the LTP decline and tau hyperphosphorylation. Increase of the intracellular calcium level, mediated by NMDA and nACh receptors, is responsible for appearance of LTP, which depends on increased in AMPA phosphorylation. Quantitative systems pharmacology (QSP) model of synaptic plasticity was developed to investigate influence of Aβ on impairment of LTP and tau hyperphosphorylation.MethodThe model describes a calcium influx in postsynapse through acetylcholine and glutamate receptors, activation of efflux from intracellular stores, activation of kinase/phosphatase cascade, tau phosphorylation and level of phosphorylation of AMPA receptors, which is associated with LTP. AD pathology is modeled by Aβ impact on receptors (inhibits nACh) and glial glutamate uptake. Model is developed step by step from simpler variants by consecutive addition of new mechanistic details, using in vitro data. In vitro data from the literature on synaptic plasticity in presence of different effectors, are used for verification.ResultThe model qualitatively describes impairment of LTP and tau hyperphosphorylation by Aβ influence and effect of receptor blockers, kinase and phosphatase inhibitors. It demonstrates that: 1) cholinergic and glutamate stimulation leads to LTP, depending on the timing of cholinergic input relative to glutamate input; 2) impaired LTP may recover due to extrasynaptic NMDA receptor blockers (e.g. memantine) or agonists of nACh receptors (e.g. SSR180711); 3) inhibitors of calcineurin decreased tau phosphorylation and recover LTPConclusionThe QSP model describes an influence Aβ on different postsynaptic mechanisms (receptors activation and kinase/phosphatase cascade, phosphorylation and dephosphorylation of AMPA receptors), which seems to underlie LTP and tau hyperphosphorylation.