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The QSP model of microglia role in tau pathology and neurodegeneration
EP39804
Poster Title: The QSP model of microglia role in tau pathology and neurodegeneration
Submitted on 24 Jan 2023
Author(s): Stepan Lerner, Maria Myshkina, Tatiana Karelina
Affiliations: InSysBio
This poster was presented at ACoP13
Poster Views: 54
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Poster Information
Abstract: Objectives: Inflammation is one of the critical components in the development of neurodegenerative diseases. Microglia cells are resident macrophages of the central nervous system.. Microglia related genes are known as risk factors of the Alzheimer’s disease (AD) and activated microglia are found in close association with tau bearing neurons [1] in the brain. Histological examination of AD brains and cell culture studies shows that the interaction of microglia with tau leads to inflammatory response [1]. Microglia becomes hypophagocytic while releasing seed-competent tau aggregates after activation of microglia phagocytosis by tau aggregate-bearing neurons [2]. We use QSP (Quantitative Systems Pharmacology) modelling to investigate the interaction of tau pathology and inflammatory state of microglia and its CSF biomarkers in AD.

Methods: The QSP model describes processes in microglia, neuron, ISF (interstitial fluid), CSF. It describes microglia activation states during stimulation and includes variables for some cytokines IL-1b, IL-6, TNFa etc, for intracellular microglia signaling (kinases and transcription factors) and receptors such as TREM2 and TLR. The compartment of neuron includes: activation kinase (p38), tau phosphorylation, tau aggregation, and degradation, tau distribution between neuron and microglia. Inflammatory state of microglia influences tau phosphorylation in neuron. Disbalance of activation of macrophages leads to neurophagy. Tau aggregation leads to the activation of inflammatory processes and induces NLRP3 inflammasome activation. QSP model is developed step by step by consecutive addition of new mechanistic details, using literature in vitro data and in vivo data for transgenic mouse. Verification and validation datasets included in vivo mice data under various conditions: TREM2 overexpression and TREM2 KO, , human data for TREM2 antibody AL002.

Results: The model correctly describes inflammatory response of microglia to stimulation by aggregated tau influence in according with mice data [1] and increase of sTREM correlated with tau markers (p-tau in CSF) [3]. Simulations reproduce correctly the observations: 1) increase of sTREM2 in CSF connected with early stage of AD in human [3] 2) tau aggregation influences NLRP3 and p38 activity and inflammatory cytokine level [1] 3) TREM2 overexpression suppressed the microglial inflammatory response, which subsequently reduces tau aggregation in 2 times via attenuation of tau kinase activity [4] 4) p38 inhibition by SB203580 reduces tau aggregation and inflammatory response in microglia [5][6] 5) TREM signaling activation by AL002 antibody reduces the IL-1β in CSF in correspondence with the data [7]

Conclusions: QSP model potentially can be applied to describe tau or microglia targeting therapy efficacy at different Alzheimer’s disease stages.
Summary: QSP model potentially can be applied to describe tau or microglia targeting therapy efficacy at different Alzheimer’s disease stages.References: [1] – PMID: 12629164
[2] – PMID: 34669475
[3] – Suarez-Calvet, 2019
[4] – PMID: 29362997
[5] – PMID: 35006531
[6] – PMID: 15013563
[7] – A Phase 1 Study of AL002 in Healthy Volunteers (poster)
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