Sevastou, I.; (2010) Ramifications of microglial activation on oligodendrocytes in in vitro models of multiple sclerosis. Doctoral thesis , UCL (University College London).

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Abstract

Oligodendrocytes are the principal target of immune attack in multiple sclerosis (MS), where the immune system attacks the myelin sheath, leading to oligodendrocyte demise, compromised axonal saltatory conduction and eventually neuronal degeneration. Microglia are also implicated in MS pathology and are present in lesions in an activated state. To study the effects of activated microglia on oligodendrocyte precursor cells (OPCs) or mature oligodendrocytes, primary cultures of microglia, oligodendrocytes, or co-cultures of the two cell populations were developed. Microglia activated with lipopolysaccharide (LPS), were toxic to OPCs and mature oligodendrocytes in co-culture. This toxicity was mediated by tumour necrosis factor α (TNF-α) released from microglia. Microglial activation with the blood-borne proteins (BBPs) fraction V albumin, fibrinogen and fibrin was also investigated. BBPs enter the brain after blood-brain barrier disruption, a typical event in MS, so their differential effect upon microglial activation and subsequently oligodendrocyte lineage cell maturation survival was studied. BBPs had distinct effects on microglial activation and oligodendrocyte cell toxicity. Fraction V albumin and fibrin were directly toxic to oligodendrocytes while microglial activation protected oligodendrocytes in co-culture. Fibrin also inhibited OPC maturation into myelinating oligodendrocytes. Fibrinogen activated microglia were toxic to OPCs and mature oligodendrocytes in co-culture. Attenuation of microglial induced oligodendrocyte death was attempted by blocking pathways of microglial activation such as the Rho-ROCK pathway and by modulating microglial activation by metabotropic glutamate receptor manipulation. Additionally, ROCK inhibition was able to attenuate LPS or BBP activated microglial expression of inducible nitric oxide synthase (iNOS). Modulation of microglial activation could prevent microglial induced oligodendrocyte toxicity and could lead to strategies to slow disease progression in MS patients by protecting mature oligodendrocytes from microglial induced death, or most importantly by enhancing survival and maturation of OPCs in MS lesions, where their recruitment to remyelinate neuronal axons is vital for disease remission.

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