Investigation into possible modulators of microglial activation

Abstract

Ageing is associated with an increase in inflammatory changes and a decline in biological function, inflammatory changes in the brain are primarily the result of activated microglia, the immune cells of the brain, and it appears that there may be several states of activated microglia associated with ageing. These stages of activation serve to function in various capacities, including increased motility, antigen presentation, phagocytosis and production of neurotoxic factors. Microglial activation is known to be potently induced by the pro-inflammatory cytokine interferon-gamma (IFN-y), a macrophage-activating factor. However the cell source of IFN-y in the central nervous system (CNS) is not known, and therefore the trigger(s) leading to age-related microglial activation are not known. One of the functional outcomes of activated microglia is the release of pro- inflammatory cytokines, which transmit signals that can lead to a deficit in synaptic function and eventual neurodegeneration. Ageing is the most significant risk factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, which is typified by a selective and progressive degeneration of neurons in the CNS. Such neurons are incapable of regeneration due, in part, to the inhibitory actions of the Nogo protein. The aims of this study were to examine the existence of multiple activation states of microglia in the brain of aged rats, determine a possible activator(s) for these microglia, investigate the possibility that infiltrating NK cells might be a source of immunomodulatory molecules in the age-associated activation of microglia and assess whether or not Nogo may be a potential immune modulatory molecule in the aged and Aβ-treated brain.