Moreover, recent human data using TNF neutralizing drugs demonstr

Moreover, recent human data using TNF neutralizing drugs demonstrated cognitive improvement in AD patients suggesting that diminished TNF levels in the mice could have contributed to the cognitive neither improvements observed. We also appreciate that dasatinib treatment Inhibitors,Modulators,Libraries may affect a number of other kinases in vitro and in vivo, and nu merous cells express Src family kinases and Abl. Non receptor Src family tyrosine kinases are expressed widely in the mammalian CNS and are known to play a role in proliferation and differentiation of the CNS. In deed, Src family kinase activities Inhibitors,Modulators,Libraries are crucial for synaptic plasticity, including learning and memory. Add itionally, there Inhibitors,Modulators,Libraries is compelling evidence that neuronal Abl activity can also mediate microgliosis in vivo, suggesting that dasatinib may also work through this mechanism to exert its anti inflammatory effects.

It is also intri guing that Abl is able to phosphorylate tau protein on Tyr 394 identified from AD brains as well as the intra cellular domain of APP to modulate signaling responses. Although we have not focused on Abl expres sion or activity in Inhibitors,Modulators,Libraries this study we appreciate that activity of this kinase is of great interest to not only the field of AD but myriad conditions in which oxidative stress associated neuron death is involved, including Parkin sons disease. However, this interest in Abl activity to regulate cell death, parkin phosphor ylation and tau phosphorylation is all based upon neuronal expression of the kinase. In deed, there is no reported expression of Abl in micro glia, to the best of our knowledge.

We expect that dasatinib actions in the brain will certainly include in hibition of not only microglial Inhibitors,Modulators,Libraries Src activity but additional Src family members expressed in microglia and other cells as well as Abl, which will have a broader target base than only a single kinase activity in microglia. This may have additional therapeutic benefits of not only anti inflammatory actions on microglia but also direct neuroprotection. We do not rule out that some of the changes we observed are not also due to inhibition of Src family kinases or other non receptor kinases, includ ing Abl in our experiments. Certainly, our staining demonstrated additional vasculature phospho tyrosine and pSrc immunoreactivity outside of the microglial immunoreactivity.

Therefore, any strategy to manipulate activity of these tyrosine kinases in the brain should be carefully considered with regard to particular cellular targets. By focusing on microglia AB interaction and demonstrating specificity of dasatinib for Src versus the related family member Lyn in vivo as well as a clear im provement in may cognitive performance, we suggest that reagents, such as dasatinib, at least be considered for anti inflammatory human testing but, more importantly, for further drug development.

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