The fibrillar form of A beta (fA beta) exerts toxic effects on neurons through mechanisms not well understood. We have shown that the aged primate cortex is selectively vulnerable to
fA beta toxicity at low concentrations. In addition to neuronal loss, fA beta induced massive activation of microglia in the aged rhesus cortex. We now demonstrate that inhibition of microglia activation abolishes fA beta toxicity. Injection or pump delivery of macrophage/microglia inhibitory factor (MIF) significantly reduced activation of microglia and the volume of damage caused by fA beta. Microglia isolated from aged rhesus cortex produced substantial reactive oxygen species when stimulated by fA beta, which was inhibited by MIF in a dose-dependent manner. This is the https://www.selleckchem.com/products/azd9291.html first definitive in vivo demonstration that the
fA beta-induced microglia activation and inflammation mediate, at least in part, its toxic effects on neurons. Combined with our earlier observations, these findings suggest that aged primate microglia may display an exaggerated inflammatory response to fA beta when compared with young microglia. (C) Selleckchem GNS-1480 2009 Elsevier Inc. All rights reserved.”
“Purpose: Molecular imaging using positron emission tomography (PET) radiotracers targeted to tumor vasculature offers a noninvasive method for early detection of tumor angiogenesis and efficient monitoring of response to anti-tumor vasculature therapy. The previous in vitro results demonstrated that the GX1 peptide, identified by phage display technology, is a tumor vasculature endotheliumspecific ligand. In this study, we evaluated a Cu-64-labeled GX1 peptide as a potential radiotracer for microPET imaging of tumor vasculature in a U87MG tumor xenografted mouse model.\n\nMethods: Macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N, N’, N ”, N”’-tetraacetic acid (DOTA)-conjugated GX1 peptide was synthesized and radiolabeled with Cu-64
(t(1/2) = 12.7 h) in ammonium acetate buffer. The Cu-64-labeled GX1 peptide was then subjected to in vitro tumor cell uptake study, small animal PET and direct tissue sampling biodistribution studies in a U87MG tumor xenografted mouse model.\n\nResults: The in vitro experiment demonstrated that Cu-64-DOTA-GX1 Selleckchem NVP-BSK805 is stable in PBS with more than 91% of Cu-64-DOTA-GX1 peptide remaining intact after 24 h of incubation. Cellular uptake and retention studies revealed Cu-64-DOTA-GX1 binds to U87MG glioma cells and has good tumor cell retention. For small animal PET imaging studies, the U87MG tumors were all clearly visible with high contrast to contralateral background at all measured time points after injection of Cu-64-DOTA-GX1 while high accumulation in liver and kidneys were also observed at early time points. The U87MG tumor uptake was determined to be the highest (7.97 +/- 0.75% ID/g) at 24 h pi.