Neurotoxicity and behavioral deficits have previously been reported in the tTA single transgenic animals. Therefore, it is important to use the tTA genotype as a control in all behavioral tests. Indeed, tTA animals showed a number of gene expression changes compared to DN animals. This could be due to insertional mutagenesis effects, direct toxicity of the tTA protein product, or interference of the tTA transcriptional activation function with endogenous transcriptional machinery. While we cannot conclude that inflammation is 4-Quinazolinamine contributing to the pathology and behavioral deficits, our results suggest that rTg4510 mice could serve as an appropriate preclinical model to test a variety of anti-inflammatory mechanisms for the treatment of tauopathies. Indeed, overexpression of fractalkine, which would be predicted to inhibit microglial activation, has been shown to reverse behavioral deficits in rTg4510 animals. Furthermore, inflammatory markers could serve as Oxymetazoline hydrochloride invaluable pharmacodynamic endpoints in this model, because the downregulation of tau with doxycycline resulted in reduced inflammation. Therefore, inflammatory markers could be used as surrogate efficacy endpoints to monitor treatments directed at tau, such as tau phosphorylation, in addition to inflammatory treatments. Doxycycline reduced inflammatory markers in as little as one week when administered to animals that already displayed robust inflammation, suggesting the treatment was not just preventing further inflammation, but resolving extant inflammation. The possibility does remain, however, that doxycyline is reducing inflammation directly, since doxycycline has been reported to have anti-inflammatory properties in its own right. However, the observation that doxycycline appears to preferentially reduce human tau levels in a particular cortical layer and this is the same layer that shows the greatest reduction in GFAP staining suggests that at least some of the reduced inflammation observed with doxycycline treatment was a result of tau reduction.In summary, we have conducted a characterization of the natural history of tau-dependent changes in gene expression in the rTg4510 mice.