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Neuroinflammation drug validation using human cells
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Neuroinflammation is a key part of the pathological process that underlies neurodegenerative diseases such as Alzheimer’s and Parkinson’s Disease, and also as is increasingly recognised, for psychiatric disorders like schizophrenia and depression. To better understand the neuroinflammatory processes underlying pathology, and to assess potential therapeutic utility, Celentyx have developed a neuroinflammation platform using human cellular models to probe cytokine/biomarker release, cell chemotaxis, phagocytosis and autoantibody binding. Assays may be suitable for evaluating modulators of ABCA7, adenosine receptors, CD33, CR1, JAK, IL-6R, GABA receptors, NLRP3, NMDA receptors, P2RX7, P2RY12, STAT3, TREM2 and others. |
Induced microglia from human monocytes (iMDM)
Microglia are resident immune cells in the brain and play a critical role in responding to pathogens and neuronal homeostasis. As a result, they can play important roles in both driving neuroinflammation and neurodegeneration, and in facilitating repair following damage. We have developed a human model system for studying microglia by differentiating monocytes (from healthy donors or patients) with a cocktail of CNS cytokines. As shown below, these cells acquire a microglial phenotype, and can be used for a range of studies including phagocytosis and cytokine release (also see our dedicated microglia page).
Microglial cytokine responses and antagonism/inhibition
Ability of test stimuli to enhance cytokine release (below, left) from monocyte-derived microglia and inhibition by a model antagonist. Concentration-dependent inhibition of cytokine release by example inhibitors enabling subsequent pharmacological analysis. A wide range of soluble factors can be measured by ELISA or Luminex.
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Microglial phagocytosis
Potential modulators of phagocytosis can be screened and their impact on phagocytosis of a range of cargos (such as myelin-basic protein, protein aggregates, beads, E.coli, neuronal cell lines) can be quantified in 96- or 384-well plate format by high-content confocal microscopy (below left shows screening over time of modulators of phagocytosis). As human monocytes are relatively accessible, patient-derived monocytes can be used to generate monocyte-derived microglia (iMDM) which can be characterised in functional assays (below right shows phagocytosis of labelled-myelin basic protein by iMDM derived from patients with schizophrenia).
Screening of modulators
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Use of patient-derived monocytes to generate iMDM
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Neuronal autoantibody binding
Several neuroinflammatory conditions are associated with the presence of antibodies that bind neuronal proteins. We have measured a cell-based binding assay that enables investigation of autoantibody binding and function.
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