We've updated our Privacy Policy to make it clearer how we use your personal data.
We use cookies to provide you with a better experience, read our Cookie Policy
EP39056
Abstract: Objectives: Amyloid beta and tau protein both have well established roles in Alzheimer’s disease (AD), forming the two hallmarks pathologies visible in postmortem AD brains as amyloid plaques and
neurofibrillary tangles (NFTs), respectively. Ab (amyloid beta) and oTau (tau oligomers) are both fundamental in the early stages of AD, but whether and how these two proteins interact is not yet established. In animal models of AD, Ab peptides and tau proteins are known to interfere with physiological mechanisms of neuronal synaptic plasticity. The concurrent application of Ab and oTau proteins impairs memory and its electrophysiological surrogate LTP (long-term potentiation), effects that may be mediated by intra-neuronal mechanisms. Changes in motor-evoked potential (MEP) amplitudes most likely represent synaptic plasticity and are thus termed LTP-like and LTD-like plasticity.
The amplitude of MEPs was increased in AD patients. Quantitative systems pharmacology (QSP) model of synaptic plasticity was developed to investigate influence of Ab and oTau on synaptic plasticity.
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 glial extracellular glutamate uptake. The influence of oTau was modelled on ER (endoplasmic reticulum) and inhibited of synaptic NMDAr. 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 impairment of LTP by Ab and oTau influence. It demonstrates that: 1) LTP with low concentration of Ab (0.5nM [1]) and oTau (9nM [1]) is not significant in comparison with baseline [2] 2) LTP with high concentration of Ab (25nM [1]) and oTau (106nM [1]) showing a clear reversal of LTP toward LTD [2] 3) extrasynaptic NMDAr blockers action by memantine with high concentration of Ab and oTau (25nM;106nM [1], respectively) does not recover LTP
Conclusions: The QSP model describes an influence amyloid beta and oTau on LTP, which may partially explain failure of amyloid and tau targeting and set up hypotheses for combinatorial treatments at
different disease stages. This QSP model may describes of clinical data. Summary: The QSP model describes an influence amyloid beta and oTau on LTP, which may partially explain failure of amyloid and tau targeting and set up hypotheses for combinatorial treatments at different disease stages. This QSP model may describes of clinical data. References: [1] - PMID: 33818905
[2] - PMID: 26757193
neurofibrillary tangles (NFTs), respectively. Ab (amyloid beta) and oTau (tau oligomers) are both fundamental in the early stages of AD, but whether and how these two proteins interact is not yet established. In animal models of AD, Ab peptides and tau proteins are known to interfere with physiological mechanisms of neuronal synaptic plasticity. The concurrent application of Ab and oTau proteins impairs memory and its electrophysiological surrogate LTP (long-term potentiation), effects that may be mediated by intra-neuronal mechanisms. Changes in motor-evoked potential (MEP) amplitudes most likely represent synaptic plasticity and are thus termed LTP-like and LTD-like plasticity.
The amplitude of MEPs was increased in AD patients. Quantitative systems pharmacology (QSP) model of synaptic plasticity was developed to investigate influence of Ab and oTau on synaptic plasticity.
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 glial extracellular glutamate uptake. The influence of oTau was modelled on ER (endoplasmic reticulum) and inhibited of synaptic NMDAr. 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 impairment of LTP by Ab and oTau influence. It demonstrates that: 1) LTP with low concentration of Ab (0.5nM [1]) and oTau (9nM [1]) is not significant in comparison with baseline [2] 2) LTP with high concentration of Ab (25nM [1]) and oTau (106nM [1]) showing a clear reversal of LTP toward LTD [2] 3) extrasynaptic NMDAr blockers action by memantine with high concentration of Ab and oTau (25nM;106nM [1], respectively) does not recover LTP
Conclusions: The QSP model describes an influence amyloid beta and oTau on LTP, which may partially explain failure of amyloid and tau targeting and set up hypotheses for combinatorial treatments at
different disease stages. This QSP model may describes of clinical data. Summary: The QSP model describes an influence amyloid beta and oTau on LTP, which may partially explain failure of amyloid and tau targeting and set up hypotheses for combinatorial treatments at different disease stages. This QSP model may describes of clinical data. References: [1] - PMID: 33818905
[2] - PMID: 26757193
Ask the author a question about this poster.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Related Posters
Virtual Patients Parallel Simulations in a Hybrid Cloud Environment
Ivan Borisov, Evgeny Metelkin, Tatiana Karelina, Oleg Demin
Wavefunction Stability Determination
Tylor
Computational Planning of Synthesis of Natural Products
Tylor
Neurodegeneration quantitative systems pharmacology modeling for analysis of multiple sclerosis therapy
Polina Pchelintseva, Anna Mishina, Tatiana Karelina
Retrosynthetic Route Planning Based on Molecular Similarity
Tylor
