Expression of almost all matrix degrading enzymes ex amined differed with the microglial activation state. There are previous reports that microglia express heparanase, as well as several selleckchem Z-VAD-FMK MMPs and cathepsins. Little is known about how LPS alters their expres sion, and almost Inhibitors,Modulators,Libraries nothing is known about the effect of IL4. We found that IL4 treatment uniquely upregulated several constitutively expressed enzymes, MMP2, Cat K, Cat S, and the MMP inhibitor, TIMP1. Inhibitors,Modulators,Libraries LPS uniquely up regulated MMP9, MMP12, MMP14, heparanase and Cat L1, but did not alter MMP2, TIMP1 or Cat B, K or S. Previously, LPS was seen to increase expression of MMP12 and MMP14 in human microglia, and MMP9 and MMP14 in murine microglia. Given the broad range of enzymes expressed by LPS treated cells, their poor invasion capacity was likely due to the lack of migration capacity.

It is an intriguing finding that microglia expressed and used different cathepsins for migration and invasion, es pecially Cat S in IL4 treated cells. Most cysteine cathep sins are lysosomal endopeptidases that are active only at acidic pH but Cat S is enzymatically active at both acidic and neutral pH and can degrade some ECM components Inhibitors,Modulators,Libraries of the CNS. Some cathepsins are ubi quitously expressed and others are more cell specific. Cat S is thought to be restricted to antigen presenting cells and can be secreted by macrophages and microglia. Cat S is expressed in unstimulated microglia and is induced in microglia following spinal cord injury, where it contributes to neuropathic pain.

There are several previous studies of microglia activation and Cat S but the results are inconsistent, and information relat ing it to IL4 treatment is very limited. IL4 increased the Cat S activity in tumor associated macrophages, and we found it selectively upregulated Cat S expression. Inhibitors,Modulators,Libraries Based upon our in vitro data, we targeted Src as a key enzyme activated down stream of AB Inhibitors,Modulators,Libraries fibril stimulation and demonstrated that a clinically available drug, dasatinib, was able to improve cognitive function while attenuating microglial activation and active Src levels in these cells. Importantly, this anti inflammatory effect did not adversely affect AB plaque load in the mice. Therefore, a directed anti inflammatory strategy targeting the particular enzymes involved in AB stimulated microgliosis may be more relevant than broad based Cox inhibition for testing during disease.

Moreover, the fact that this tyrosine kinase inhibition strategy was effective even during advanced stages of dis www.selleckchem.com/products/BAY-73-4506.html ease in the mice suggests that this particular form of anti inflammatory therapy is viable during advanced dis ease in contrast to Cox inhibition. We are aware that the effect of decreasing microglial active Src and brain TNF levels does not necessarily prove that these changes were responsible for the improved cognitive performance.