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Investigation of inflammation during Alzheimer
EP38465
Poster Title: Investigation of inflammation during Alzheimer's disease by quantitative systems pharmacology model
Submitted on 09 Mar 2022
Author(s): Andrey Masliukov, Tatiana Karelina
Affiliations: InSysBio
This poster was presented at ACoP12
Poster Views: 302
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Poster Information
Abstract: Background: Inflammation is one of the critical components in the development of neurodegenerative diseases. Microglia are the resident macrophages of the central nervous system. It plays a key role in the development of inflammation in the brain. Alzheimer’s disease pathogenesis is driven by the production and deposition of the β-amyloid peptide (Aβ). It increases the activation of microglia cells and switches them from resting (M0) to activating (M1 or M2) state and the release of cytokines. The role of microglia in AD progression is unclear, with conflicting reports regarding their detrimental or protective contribution to the disease. Therefore, understanding the role of microglial cells activation and inflammation in the progress of AD may help in the treatment of this disease. In order to correctly predict the effects of various therapeutic methods, it is necessary to understand the dynamics of microglia cells.
The aim of our study was to create a translational quantitative systems pharmacology model to study the microglia during the inflammation and amyloid accumulation.

Methods: The model describes microglia resting state and two activated (pro-inflammatory M1 and anti-inflammatory M2) states, apoptosis of microglia cells, response of microglia to LPS, oligomeric and fibrillar amyloid and cytokines, distribution of cytokines from the brain into cerebrospinal fluid and blood. The model was calibrated on available literature data: in vitro influence of LPS, cytokines in apoptosis of microglia, Aβ stimulated synthesis of IL1b, TNFa, intracerebroventricular (i.c.v.) and peripheral injection of radio-labeled cytokines, i.c.v injection of LPS, baselines of cytokines in mice brain. Model was calibrated on available literature data: of cytokines (TNF, IL1, IL6, IL10) in APP transgenetic (TG2576) mouse AD models [1]. To describe the transgenic mouse, we described the accumulation of amyloid by explicit function

Results: The model correctly described apoptosis of microglia stimulated by LPS and inhibited by TGFb in vitro, the activation of pro-inflammatory microglia by LPS and amyloid in vitro It satisfactory describes an increase in the concentration of pro-inflammatory cytokines during the development of LPS-induced inflammation in healthy mice. Model predicts increase in inflammatory cytokines (TNFa and IL6) and no increase in anti-inflammatory (IL10) with amyloid accumulation in transgenic APP mice. Model correctly describes decrease of the concentration of IL-1 with a decrease in the concentration of amyloid by treatment with phenserine. It also predicts decrease of the concentration of other pro-inflammatory cytokines (TNFa) with a decrease in the concentration of amyloid, which does not agree with the data in the article [2]. Accordingly, it is necessary to study more specifically the states and markers of microglia. Clear of Aβ also led to general activation of microglia (CD68 labeled) in treatment of mouse by BASE1 inhibitor.

Conclusions: This QSP model can be used to predict the response of microglia to various conditions caused by neurodegenerative diseases.
Summary: This QSP model can be used to predict the response of microglia to various conditions caused by neurodegenerative diseases.References: 1. Patel N.S. [and oth.]. // Journal of Neuroinflammation. 2005. (2). P. 1–10.
2. Lilja A. M. [and oth.]. // PLoS ONE. 2013. № 3 (8).
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