Hooper, C.; (2004) Microglial signalling cascades associated with stroke and Alzheimer's disease. Doctoral thesis , University of London.

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Abstract

Microglia, the resident macrophages of the brain, were originally assumed to be passive cells, however increasing evidence suggests that microglia play an active role during development and in neurological disorders. Activated microglia release a variety of toxic inflammatory mediators including reactive nitrogen species, cytokines, glutamate and oxygen free radicals, all of which exert a detrimental effect on neuronal survival if secretion is sustained. Microglial responses depend on the signals received from the surrounding microenvironment. Therefore, in this thesis the effects of albumin, chromogranin A (CgA), ?-amyloid (A?), ischaemia and combined insults (ischaemia plus albumin or ischaemia plus A?) on microglial signalling have been investigated because these activators are associated with the pathology of stroke and/or Alzheimer's disease. Briefly, albumin was found to induce iNOS expression, to cause the release of glutamate and to elicit a calcium-dependent proliferative response in microglia; events that were mediated by a possible interaction with myosin IX. Interestingly, peritoneal macrophages were unresponsive to the same concentrations of albumin. CgA and A? triggered microglial signalling via scavenger receptor-dependent mechanisms. Both activators caused microglia to undergo mitochondrial depolarisation, which precipitated apoptosis. CgA, but not A?, also induced iNOS expression and glutamate release. CgA-induced iNOS expression was mediated by the Src kinase-dependent phosphorylation of ERK. Ischaemia per se did not elicit any discernable effects on microglial signalling. However, microglia subjected to ischaemia followed by albumin treatment endured mitochondrial depolarisation, which led to apoptosis. Similarly, ischaemia followed by A? treatment potentiated the levels of microglial apoptosis and mitochondrial depolarisation induced by A? alone. A common characteristic displayed by microglia subjected to albumin, CgA, A?, or ischaemia was the ability to induce neuronal death. Thus, manipulation of microglial signalling pathways to reduce reactivity and neurotoxicity may provide novel therapeutic strategies for the amelioration of neurodegeneration in disorders such as stroke and Alzheimer's disease.

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