Biomarkers of Neuroinflammation Proceedings of a Workshop (2018) / Chapter Skim
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3 State of the Science of Neuroinflammation in Central Nervous System Disorders
3 State of the Science of Neuroinflammation in Central Nervous System Disorders
Pages 15-24
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From page 15... ...
. • Identifying the signals involved in synaptic pruning may unveil biomarkers and therapeutic targets for many CNS diseases (Stevens)
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From page 16... ...
Landreth added that all microglia derive from cell proliferation and self-renewal of these progenitors, but said that the biology around these progenitors and the natural history of microglia, including metabolic changes, have been poorly explored. Similar to the way peripheral immune cells function, microglia defend against damage by continuously surveilling the brain for perturbations.
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From page 17... ...
interact with astrocytes, although the relationship between these two cell types and the effect on neuroinflammatory disease is not well understood. Landreth noted that in addition to resident microglia, an inflammatory subset of blood-borne monocytes infiltrates the brain in a number of CNS disorders, and then acquires microglia markers and produces inflammatory cytokines within 72 hours that make them indistinguishable from resident microglia (Sieweke and Allen, 2013)
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From page 18... ...
He said that when stimulated, microglia enter a responding stage with a number of different phenotypes that may alternatively internalize toxic substances, take on a migratory phenotype, release proinflammatory cytokines or reactive oxygen species, or release factors involved in repairing, such as neuroprotective or angiogenic factors, anti-inflammatory cytokines, prostaglandins, microvesicles, and microRNAs or miRNAs (Loane and Byrnes, 2010)
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From page 19... ...
The normal pruning process becomes aberrantly regulated in a host of different neurological diseases, contributing to synapse loss and dysfunction, said Stevens, adding that defects in pruning or remodeling may underlie neurological, neurodevelopmental, and neuropsychiatric disorders, including schizophrenia and autism, as well as in diseases of aging, such as AD. Synapse loss in AD appears to occur at an early stage of the disease, before overt inflammation, and is correlated to cognitive dysfunction.
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From page 20... ...
They also undergo extremely low rates of transcytosis or vesicle-mediated trafficking, and express proteins that pump out small lipophilic molecules that have gotten into the brain and selectively transport specific metabolites into the brain. Finally, they express low levels of molecules that in other tissues are responsible for binding immune cells to facilitate their entry into those tissues.
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From page 21... ...
These observations led Daneman to hypothesize that upregulation of peripheral endothelial genes leads to BBB disruption during disease, at least in part because of a loss of endothelial–pericyte interactions. A screen in his lab for candidate genes that disrupt cellular barriers led to the identification of a family of genes (the EHD family)
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From page 22... ...
Epidemiological studies show that increased leakage of plasma proteins from inside the vessels to the surrounding tissue correlates with worsening pathology and worse prognosis, she said. Her lab aims to identify the peripheral triggers and molecular determinants of this pathological process, which could lead not only to the development of new imaging tools to image the neurovascular interface but also to new therapeutics, animal models, and biomarkers.
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From page 23... ...
What they found is that microglia are the main cell targets of fibrin in the CNS through the binding of one of these epitopes to the microglia CD11b/CD18 integrin receptor (complement receptor 3) , while another epitope in the fibrin molecule binds to platelets to cause coagulation (Adams et al., 2007)
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