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Quantitative mechanistic model for amyloid beta and tau protein role in synaptic plasticity
EP34501
Poster Title: Quantitative mechanistic model for amyloid beta and tau protein role in synaptic plasticity
Submitted on 25 Nov 2020
Author(s): Stepan Lerner, Tatiana Karelina
Affiliations: InSysBio
This poster was presented at ACoP20
Poster Views: 168
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Poster Information
Abstract: Quantitative mechanistic model for amyloid beta and tau protein role in synaptic plasticity



Stepan Lerner, Tatiana Karelina

InSyBio, Moscow, Russia



Objectives:

Current therapies for amyloid beta (A) do not modify the progression of the Alzheimer’s disease (AD). Amyloid hypothesis of AD is still debated. One of the most important property of neuron cells is its synaptic plasticity. Most of the physiological studies of synaptic plasticity investigate LTP (long-term potentiation) and LTD (long-term depression). The synaptic plasticity seems to underlie memory and learning formation. In animal models of AD, A inhibits LTP. An increased intracellular calcium level, mediated by NMDA and nACh receptors, is responsible for appearance of LTP, which is determined by increased AMPA receptor phosphorylation. These processes may contribute to tau hyperphosphorylation, further pathology progression. Understanding of these synaptic processes is particularly important for better prediction of cognitive outcomes in clinical trials. Quantitative systems pharmacology (QSP) model of synaptic plasticity was developed to investigate influence of amyloid beta on receptors governing LTP and state of tau protein.



Methods:

The model describes calcium influx in postsynapse through acetylcholine and glutamate receptors. Type of stimulation varies by changing the timing between cholinergic input and glutamatergic input. The model describes activation of kinase/phosphatase cascade, tau phosphorylation and level of AMPA receptors phosphorylation. The level determines the synaptic plasticity. A impairment of synaptic plasticity is modelled through impact on receptors and glial extracellular glutamate uptake. Potential A targeting therapy is represented as A washout. At the time of washout, A concentration is set to zero. Model is developed step by step by consecutive addition of new mechanistic details, using in vitro data and in vivo mouse data. In vitro data from the literature concerning synaptic plasticity (LTP) under various conditions are used for verification.



Results:

The model qualitatively describes LTP and its decrease in presence of A (Figure 1). It demonstrates that: 1) amyloid effect on LTP in such a system is partially irreversible, and amyloid washout does not lead to complete recovery of LTP 2) memantine protects from decrease of LTP 3) LTP recovers after exNMDAr blockers action, because memantine decreases binding glutamate with receptors and, thus, decreases calcineurin activity 4) at small concentration of amyloid beta (10nM) with memantine, there is a complete rescue of LTP and decrease of tau phosphorylation; at medium concentration of A (10nM50nM<100nM), with memantine recover LTP and decrease tau phosphorylation only after A washout; after influence of high A concentration (>100nM) memantine does not provide recovery of LTP even after amyloid washout, but tau phosphorylation may decrease.



Conclusions:

The model demonstrates a partial irreversibility effect of amyloid beta on LTP even on short times, which may partially explain failure of amyloid targeting and set up hypotheses for combinatorial treatments at different disease stages. This QSP model may connect models of proteinopathies with cognitive outcome.
Summary: The model describes cholinergic and glutamate stimulation that leads to LTP;
• LTP recovers completely after washout of oAβ and with combination memantine + washout;
• LTP recovers from blockers impact on extrasynaptic NMDA receptors;
• In perspective, this model can further be adapted for searching of optimal combination therapy
targeting amyloid and synaptic processes.
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