The QSP model of TREM2 influences on inflammatory state of microglia in Alzheimer’s disease

Abstract

AbstractBackgroundInflammation is one of the critical components in the development of neurodegenerative diseases. Microglia is the resident of macrophages of the central nervous system. In the AD brain, microglial cells are found in close association with amyloid beta deposits. Histological examination of AD brains as well as cell culture studies have shown that the interaction of microglia with fibrillar amyloid beta leads to their phenotypic activation. 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. The QSP model was developed to investigate influence of TREM2 on inflammation of microglia.MethodsThe model describes microglia resting state, phagocytosis, TLR, P2×7 and TREM2 receptors, kinases, intracellular signaling pathways, apoptosis of microglia cells, response of microglia to LPS, oligomeric and fibrillar amyloid and cytokines (IL6, IL1b, TNFa), distribution of cytokines from the brain into cerebrospinal fluid and blood.ResultsThe model correctly describes decreased phagocytosis, increased cytokine and pro‐inflammation factors with influence of amyloid beta and TREM2 KO during LPS‐induction. It demonstrates that: 1) TREM KO leads to decrease of phagocytosis [1] 2) Ab influence on TREM2 leads to increase of inflammatory cytokine level [2] 3) Inhibitor of PI3K (LY294002) decreases phagocytosis in signaling pathway (PI3K/FoxO/phagocytosis) [3].ConclusionsThis QSP model can be used to predict the response of microglia to various conditions caused by neurodegenerative diseases and therapies targeting microglial state.[1] – PMID: 30548312[2] – PMID: 33065553[3] – PMID: 28842601