Piers, T. M.; East, Emma and Pocock, J. M.
Fibrin and fibrinogen cause neuron non-cell autonomous degeneration.
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Microglia are the resident immune cells of the central nervous system (CNS), patrolling the parenchyma returning homeostasis to imbalanced areas via phagocytosis. Excessive microglial activation has been implicated as a causal factor of neuroinflammation and neurodegeneration via persistent release of pro-inflammatory factors (Gao et al.
2003). Blood brain barrier (BBB) disruption observed in chronic neurological disorders allows influx of blood-borne proteins including fibrinogen into the CNS parenchyma resulting in deposition of fibrin, implicated in neuroinflammation (Paul et al. 2007). The blood protein
influx has been targeted as a potential cause of excessive activation of microglia leading to neurodegenerative signalling cascades and disease progression (Hooper et al. 2009). Here direct exposure of fibrinogen to cerebellar granule cell (CGC) cultures caused significant neuronal
death within 24 hours. However an increase in neuronal death after fibrin stimulation was only observed after 48 hours, comparable with the classic microglial activator lipopolysaccharide (LPS). Fibrinogen also has potential as an indirect neurotoxin as it produced an activated
microglia phenotype. Supporting this, we show fibrinogen conditioned microglia medium caused extensive CGC death to a level comparable with fibrin or LPS. There was also significant induction of pro-inflammatory factors from both primary microglia and CGC cultures after exposure to fibrin or fibrinogen. The increase of these factors in CGC cultures was attributed to microglia because leucine methyl ester (LME) depletion of microglia significantly attenuated the response. We propose that both fibrin and fibrinogen have the potential to cause indirect neurotoxicity via a microglia mediated pathway involving pro-inflammatory factors, but only fibrinogen is directly neurotoxic.
||Microglia; immune cells; central nervous system; parenchyma; homeostasis; phagocytosis; neuroinflammation; fibrinogen; neurodegeneration;
||Science > Life, Health and Chemical Sciences
||08 Oct 2009 10:31
||24 Oct 2012 03:57
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