These observations do suggest that there are differences in the way different brain regions process and respond to C100 and/or Ab. Previous Regorafenib 755037-03-7 studies have tried to determine why the cerebellum is less vulnerable to AD pathology. It has been shown that the cerebellum contains all of the necessary proteins to produce Ab, and that plaques do eventually appear in the cerebellum as AD pathology advances, indicating that the cerebellum is capable of producing amyloid pathology. Nonetheless, the cerebellum consistently has fewer plaques and lower levels of insoluble Ab and intracellular Ab42 than other brain regions that are primarily affected in AD such as the hippocampus and cortex. It seems that the cerebellum is better equipped to prevent AD pathology from progressing. A recent study reported that secreted metabolites produced from cerebellar neurons reversed AD brain pathology in AD transgenic mice, while metabolites from hippocampal neurons exacerbated pathology. The exact proteins or pathways involved in the protection of the cerebellum in AD are not yet known, but it has been suggested that this may be specifically due to enhanced clearance or degradation of Ab. The present data suggest an alternative hypothesis, that cerebellar cells may be intrinsically less responsive to the presence of Ab and/or C100. Future research is needed to further examine why AD brain pathology develops differently in different brain regions as this could help determine what initiates the development of AD brain pathology. Vectors expressing the C100 transgene were more effective at consistently producing higher amounts of Ab than vectors directly expressing Ab transgenes, both in vitro and in vivo. This most likely resulted from the more physiological method of production of Ab from C100, in comparison to the non-physiological production by direct expression of Paclitaxel either Ab40 or Ab42. Direct expression of Ab may not be optimal for Ab accumulation, possibly due to Ab production occurring in the incorrect sub-cellular location. Previous in vitro studies have shown that fusing Ab and C100 to a signal protein that directs expression in the secretory pathway greatly increases the amount of Ab detected after plasmid 
transfection, hence suggesting that sub-cellular location of Ab may be important for expression. A further aim of this study was to determine if the effects of transduction with rAAV2 vectors expressing APP fragments were exacerbated at 6 months post-injection in comparison to 3 months post-injection. This was not found to be the case in either brain region as less extensive pathological changes were observed at 6 months post-injection. The level of transduction was similar at 3 and 6 months post-injection, therefore the less extensive pathology observed at 6 months post-injection is unlikely to be a result of any technical issues associated with long-term transduction. Instead, it is possible that brain regions may have adapted to the long-term expression of C100 and/or Ab and as a result became better equipped to deal with the consequent pathology, such as by increasing levels of Ab degrading enzymes or increasing antiinflammatory proteins. However, further studies are necessary to confirm this hypothesis. In conclusion, the use of viral vectors to over-express Ab and C100 is a promising technique with which to examine the consequences of Ab expression in mature CNS tissues in vivo.