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Description of amyloid beta influence on synaptic plasticity and tau hyperphosphorylation by mechanistic quantitative systems pharmacology model
EP32845
Poster Title: Description of amyloid beta influence on synaptic plasticity and tau hyperphosphorylation by mechanistic quantitative systems pharmacology model
Submitted on 28 Jul 2020
Author(s): Stepan Lerner, Tatiana Karelina
Affiliations: InSysBio, Moscow, Russia
This poster was presented at AAIC Virtual Event
Poster Views: 37
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Poster Information
Abstract: Description of amyloid beta influence on synaptic plasticity and tau hyperphosphorylation by mechanistic quantitative systems pharmacology model

Background. Long-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 impact on decline of LTP and tau hyperphosphorylation. An increased intercellular 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 amyloid beta on impairment of LTP and tau hyperphosphorylation in various cellular processes.
Methods. The model describes a calcium influx in postsynapse through acetylcholine and glutamate receptors, activation of kinase/phosphatase cascade, tau phosphorylation and level phosphorylation of AMPA receptors. Phosphorylation of AMPA receptors is associated with LTP. AD pathology is modeled by amyloid beta impact on receptors and glial glutamate uptake. Influence of amyloid beta on NMDAr, nAChr and glial uptake - impairs the synaptic plasticity and increase tau phosphorylation. 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.
Results. The model qualitatively describes impairment of LTP and tau hyperphosphorylation by amyloid beta influence and results 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) LTP recovers from blockers impact on extrasynaptic NMDA receptors and agonists influence on nACh receptors 3) inhibitors of calcineurin decreased tau phosphorylation and recover LTP
Conclusions. The QSP model describes an influence amyloid beta in different postsynaptic mechanisms (receptors activation and kinase/phosphatase cascade, phosphorylation and dephosphorylation of AMPA receptors), which seems to underlie LTP and tau hyperphosphorylation.
Summary: The model describes cholinergic and glutamate stimulation that leads to LTP or LTD, depending of
the timing of cholinergic input relative to glutamate input;
• oAβ affect on LTP and tau phosphorylation increase;
• LTP impaired by oAβ recovers after PP2b inhibition;
• LTP recovers from blockers impact on extrasynaptic NMDA receptors and agonists influence on
nACh receptors;
• In perspective, this model can further be adapted for searching of optimal therapy.
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