, 2006, ABT 888 Long et al., 1998, Ogura et al., 1994 and Peters et al., 2010), but less is known about phenotype changes in different regions of the

aged mouse brain. Our results are in accord with a recent study describing regional variation in expression levels of immunoregulatory molecules in the healthy adult mouse brain. De Haas et al. showed that regional differences between microglial phenotypes in the adult mouse brain are subtle: expression levels of surface markers such as CD11b, CD40 and the fractalkine receptor CX3CR1 appeared higher in the microglia of the spinal cord and cerebellum than the hippocampus (De Haas et al., 2008). In our study all functional markers tested displayed the greatest increase in expression with age in white matter regions, particularly in the cerebellum, identifying a clear trend Baf-A1 in phenotype changes along the rostro-caudal axis in the aged mouse brain. Phenotype changes in microglia are well described in response to acute and chronic injury or disease, but only a few studies have looked at differential responsiveness to the grey matter versus

the white matter along the rostro-caudal neuraxis. Trauma-induced lesions lead to a greater microglial response in the spinal cord than the cortex or corpus callosum and the spinal white matter exhibited a greater microgliosis than spinal grey matter (Batchelor et al., 2008 and Schnell et al., 1999a). Regional differences in responsiveness to inflammatory stimuli are partly responsible for these observations, as stereotaxic injections of recombinant cytokines into the striatum fail to evoke a robust response, while similar injections into the spinal cord or brainstem are associated with BBB breakdown, microgliosis and secondary tissue damage (Campbell et al., 2002, Phillips

and Lampson, 1999, Phillips et al., 1999 and Schnell et al., 1999b). This regional difference in responsiveness to inflammatory stimuli is also evident in EAE, which targets the spinal cord rather than more rostral regions of the brain, such as the forebrain (Sun et al., 2004). Collectively, these studies suggest that the caudal and white matter regions of the CNS are more responsive and therefore more vulnerable to inflammatory stimuli. Our study suggests that the differential sensitivity of these microglial populations many also applies to the ageing process. We show that in the aged brain there is a greater up-regulation of CD11b, CD11c, CD68, F4/80 and FcγRI in white matter than in grey matter and more in caudal areas than rostral areas. These data are in agreement with previous studies in the aged rat brain suggesting a rostral caudal gradient of microglial activation (Kullberg et al., 2001). It has been previously reported that the microglia of the white matter express greater levels of microglia associated molecules with age than those of the grey matter (Kullberg et al.