January 13, 2014

Dying cellsaggregated proteins activate resting

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Unformatted text preview: ctivated in response to pathogen invasion or tissue damage Microglia sense foreign body / cell death/ aggregate they go to work / activated/ trying to get rid of the body Common features - Inflammation more cell death, cytokines release, mircroglia activation We need mircroglia to be activated 1. Dying cells/aggregated proteins activate resting microglia T 2. Phagocytic microglia when microglia secrete pro-inflammatory get activated, they release pro cytokines and ROS inflamotory 3. If uncontrolled, toxic agents cytokines contribute to the loss of surrounding neurons BBB keep most 4. Systemic immune system foreign bodies / becomes essential to when microglia get Cytokines at activated , high conc — control local inflammation. Detrimental effect lead to cell endolethial cells, 5. Blood-derived monocytes death break down BBB infiltrate the damaged endothelium and differentiate into macrophages which T engulf debris, secrete growth When we have microglia, increase amt of cytokines— factors and anti-inflammatory causing more cell death. cytokines, and suppress Abbreviations: IGF-I, insulin-like growth factor I; IL, interleukin; ROS, reactive oxygen microglial activation. species; TCR, T cell receptor; TNF, tumor necrosis factor. Nature Reviews Neurology 6, 405-410 (July 2010) Immune activation in neurodegeneration • TLR3 – toll like receptor 3 TLR3 in MS Microglia in stroke Immunology, 129, 154–169 Microglia in AD Macrophages in MS Increased inflammatory components in Neurodegenerative disorders Microglia activated / upregulated in stroke, and AD , macrophages in MS, TLR3 in MS Common features - Inflammation Microglia can get rid of AB ,they stay activated/cell death with all cytokines / can come from endogenous factors • Sustained inflammation can cause cell death by production of • • • • neurotoxic factors that amplify underlying disease states Stimulus may result from environmental factors or the formation of endogenous factors (e.g. protein aggregates) In AD microglia respond to the presence of A plaques and neurofibrillary pathology Proinflammatory cytokines are produced such as IL-1 and TNF which may contribute to the neurodegenerative process Other neurodegenerative disorders showing inflammation involvement are PD, ALS and MS Common Therapeutic Implications • Currently no treatments for neurodegenerative diseases • • • • that will halt the disease process Some treatments do slow the course of the disease Treatments may be either disorder specific or may be useful for more than one disorder Because extensive neuronal degeneration and death occurs prior to diagnosis, treatments restoring function are unlikely Potential for preventing or delaying disease onset in those at risk due to genetic and/or environmental factors ways to treating neurodegenrative disorders Mattson et al. Nature Reviews Neuroscience 7, 278–294 (April 2006) | doi:10.1038/nrn1886 Risk of neurodegeneration can be modified by lifestyle Mattson et al. Nature Reviews Neuroscience 7, 278–294 (April 2006) | doi:10.1038/nrn1886...
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