We have previously shown that during chronic neurodegeneration, microglia are primed by disease to produce exaggerated sickness and CNS inflammatory responses to systemic stimulation with the TLR4 agonist LPS (Combrinck et al., 2002 and Cunningham et al., 2005a). The term microglial priming is based on early descriptions of macrophage priming in which pretreatment with IFNγ primes macrophages to produce more robust

responses to LPS (Johnson et al., Selleck isocitrate dehydrogenase inhibitor 1983 and Pace et al., 1983). Though a CNS priming factor has not yet been identified, evidence for similar in microglial priming effects, and exacerbation of pathology, has since been provided by researchers in many models of CNS pathology, including Parkinson’s disease (Godoy et al., 2008), prion disease (Cunningham et al., 2009), Wallerian degeneration (Palin et al., 2008) ageing (Godbout et al., 2005 and Barrientos et al., 2006), ALS (Nguyen et al., 2004), AD (Sly et al., 2001 and Kitazawa et al., 2005) and stroke (McColl et al., 2007). Thus systemic inflammatory events can accelerate neurodegenerative p38 MAPK inhibitor disease and we have recently shown that AD patients who suffer systemic inflammatory events, including infections,

show more rapid progression of cognitive decline (Holmes et al., 2003 and Holmes et al., 2009). The demonstration here that animals primed by neurodegeneration also mount exaggerated IL-1β and type I interferon responses to systemic challenge with poly I:C indicates that hyper-reactivity of these primed cells is not specific to LPS challenges. This finding therefore adds TLR3 activation to the list of pattern recognition receptors likely to be capable of exacerbating neurodegenerative disease. While this might have been predicted from our prior work with LPS/TLR4 (Cunningham et al., 2009), its demonstration is significant. We have made repeated challenges with poly I:C

to demonstrate acute, reversible, exacerbations of neurological function whose magnitude depends on the severity of the underlying pathology, and have shown that these repeated selleck compound challenges also accelerate disease in a cumulative manner. The repeated challenge strategy was made possible by the demonstration that these repeated treatments do not produce tolerance to poly I:C in behavioural (Cunningham et al., 2007) or peripheral type I interferon (Supplementary data) responses. Thus, 3 challenges do not appear to induce an inflammatory phenotype distinct from that induced by a single challenge. We also show that a single poly I:C challenge is sufficient to induce an acute increase in apoptosis (Fig. 8) and that three challenges are insufficient to produce any lasting impairment in normal animals (Fig. 7).