Session Title: Inflammation
CD14 MEDIATES MICROGLIAL ACTIVATION BY FIBRILLAR Aβ
E. Reed-Geaghan, P. Cramer, G. Landreth
Microglia, the principal immune effector cells of the brain, recognize fibrillar forms of Aβ (fAβ) that comprise the plaques of Alzheimer's disease through a multi-receptor complex containing CD36, CD47, and the α6β1 integrin. We demonstrate that CD14 functions as a member of this cell surface receptor complex. Microglia deficient in CD14 show reduced reactive oxygen species (ROS) production and phagocytosis following fAβ exposure. The fAβ-stimulated activities of Src and Vav, as well as the membrane association of Rac are reduced in CD14-deficient microglia. The induction of phagocytosis and ROS production requires parallel signaling through the p38 MAPK pathway, as inhibition of this pathway blocks fAβ-stimulation of these biological responses. Significantly, p38 activity is reduced in CD14-deficient microglia. Knocking out CD14 in the APPswe/PSENdE9 animal model of Alzheimer's disease reduced Aβ deposition, as measured by ELISA. In addition, microglial activation, measured by CD45 immunoreactivity, was reduced in CD14-/- mice. In summary, we have identified CD14 as a member of the receptor complex for activation of microglia by fibrillar Aβ and show this influences deposition in an animal model of the disease.