Depletion of microglia with QD Sap resulted in protection against microglia mediated Ab toxicity. Our finding that QDs are selectively taken up by microglia is consistent with previous observations that QDs were localized to macrophages and microglia that infiltrate experimental gliomas. However, in con trast Veliparib PARP inhibitor to the previous study, which suggested that QDs were phagocytosed Inhibitors,Modulators,Libraries by macrophages and microglia, our data indicate that QDs enter microglia via receptor binding and clathrin mediated endocytosis. In eukar yotes, macromolecules enter the cell in membrane bound vesicles either via phagocytosis or pinocytosis. Phagocytosis occurs by an actin dependent mechanism and is usually independent of pH gradient and clathrin, whereas pino cytosis occurs by at least four basic mechanisms, macro pinocytosis, clathrin mediated endocytosis, calveolae mediated endocytosis, and clathrin and calveolae inde pendent endocytosis.

Interestingly, the uptake of soluble Ab by microglia was found to be mediated through a nonsaturable, fluid phase macropinocytic mechanism that is distinct from phagocytosis and recep tor mediated endocytosis. The size of QDs, which range from 10 100 nm Inhibitors,Modulators,Libraries in diameter, makes it unlikely that QDs enter microglia via phagocytosis. Indeed, the blockade of QD entry by balifomycin, chlorpromazine, and cytochalasin B provide strong evidence that QDs are taken up by microglia via clathrin mediated endocy tosis. Clathrin mediated endocytosis occurs in all cell types.

However, blocking the MSR 1 or mannose recep tor with specific inhibitors or antibodies prevented the uptake of QDs, indicating that the selective targeting Inhibitors,Modulators,Libraries of QDs to microglia requires their binding Inhibitors,Modulators,Libraries to microglia specific receptors. We cannot exclude that other micro glial receptors such as Fc receptors, complement recep tors, and Toll like receptors might also mediate the endocytosis of QDs by microglia. Additional studies are needed to fully characterize the potential binding sites of QDs on the microglial surface. The unique optical properties of quantum dots, such as high quantum yields, large molar extinction coefficients, size dependent tunable emission and high photostability, make them appealing as fluorescent probes for biological imaging. On the other hand, because of their size range, QDs are also very suitable for manipulations at the mole cular level, offering new approaches Inhibitors,Modulators,Libraries for the delivery of potent bioactive agents.

Microglia may have roles in the pathogenesis of various CNS diseases, including multiple sclerosis, Alzheimers disease, Parkinsons disease, and amyotropic lateral sclerosis. Our finding that cer tain sizes of QDs selectively target microglia provides a novel platform to probe and modulate biological pro cesses in microglia and may lay the foundation for the development of QD inhibitor Paclitaxel based reagents that can modulate specific signaling pathways in microglia.