Microglial signalling cascades in neurodegenerative disease

Activated microglia release a number of substances, the specific cocktail released depending on the stimulus. Many of the substances released by microglia also serve to activate them, suggesting the presence of a number of autocrine/paracrine loops. Because of the low density of microglia present in the normal brain, such autocrine/paracrine loops may not be significant but during the initiation and ongoing states of neurodegeneration, the increased concentrations of microglia may allow the activation and escalated stimulation of these feedback pathways. The activation of p38 MAPK by A beta and cytokines may be part of a microglial autocrine loop which results in the fueling of the microglial inflammatory response. A novel class of cytokine suppressive anti-inflammatory drugs (CSAIDs) inhibit the activation of p38 kinase (Bhat et al., 1998) suggesting this kinase plays a key role in transducing microglial responses to activation stimuli (Badger et al., 1996).