Membrane microdomains (rafts and caveolae) represent multiprotein complexes assembling proteins involved in the regulation of signal transduction. We have evaluated the role of prion protein, cycloxygenase 2 (cox-2) and prostacyclin synthase (PGIS) as components of rafts and caveolae in cultured neuronal cell (GN 11) and in human endothelial cells, demonstrating their role in the control of cell survival and angiogenesis (1-3). These proteins have also a role in triggering inflammatory processes. In particular the association COX-2 / PGIS within caveolae represents a powerful stimulus for inflammation. We have also evaluated criteria to select specific COX-2 inhibitors to control inflammation and neurodegeneration, confirming that while some COX-2 inhibitors as VIOXX are to be avoided because they inhibit PGIS, thus decreasing the synthesis of PGI2, a powerful vasodilator, celebrex can be used more safely because has little effect on PGI2 synthesis (Griffoni et al Selective inhibition of prostacyclin synthase activity by rofecoxib, J. Cell Mol. Med. in press).We are evaluating the role of the conversion of prion protein to the form scrapie in triggering neurodegeneration preceded by inflammation and we are screening specific COX-2 inhibitors based on evaluation of PGIS inhibition. A second approach to control inflammatory neurodegeneration is based on the use of a selective micro RNA silencing cox-2 gene which we have recently identified and used to inhibit proliferation and invasiveness of colon cancer cells (4). Our working hypothesis regards the involvement of modification of prion protein structure initiating a brain inflammatory process which in turn induces COX-2 gene sustaining chronic inflammation and neurodegeneration.