The innate immune receptor CD14 mediates microglial activation in Alzheimer's disease

Alzheimer's disease (AD) is characterized by the presence of beta-amyloid (Abeta) plaques and neurofibrillary tangles, and is accompanied by a robust inflammatory response mediated by microglia, the brain's immune cells. Microglia are intimately associated with the plaques and interact with fibrillar Abeta (fAbeta) through an ensemble of surface receptors including the alpha6beta1 integrin, CD36, CD47, and the class A scavenger receptor. These receptors act in concert to initiate intracellular signaling cascades and phenotypic activation of these cells. However, it is unclear how engagement of this receptor complex is linked to the induction of an activated microglial phenotype. We found this response requires the participation of Toll like receptors (TLRs) and the co-receptor CD14. The response of microglia to fAbeta is reliant upon CD14, which acts together with TLR4 and TLR2 to bind fAbeta and to activate intracellular signaling. Microglia lacking these receptors could not initiate a Src-Vav-Rac signaling cascade for reactive oxygen species (ROS) production and phagocytosis. The fAbeta-mediated activation of p38 MAPK also required CD14, TLR4, and TLR2. Inhibition of p38 abrogated fAbeta-induced ROS production and attenuated the induction of phagocytosis. Microglia lacking CD14, TLR4, and TLR2 showed no induction of phosphorylated IkappaBalpha following fAbeta. These data indicate these innate immune receptors function as members of the microglial fAbeta receptor complex and identify the signaling mechanisms whereby they contribute to microglial activation. We extended these studies on the innate immune system in the inflammatory component of AD by crossing CD14-knockout mice to the APPswe/PSEN1dE9 AD mouse model. CD14 deletion reduced insoluble but not soluble levels of Abeta in the brain, corresponding to decreased plaque load resulting from decreased number and size of Thioflavin S-positive plaques. Moreover, APPswe/PSEN1dE9 CD14-/- mice had increased levels of the pro-inflammatory cytokine genes Tnfalpha and Ifngamma, decreased levels of the alternative activation markers Fizz1 and Ym1, and increased expression of Il-10, reflective of their conversion into an alternative M2b activation state. These changes in inflammatory cytokines alter the expression of various Abeta degrading enzymes or Abeta clearance proteins. These data suggest that CD14 is a critical regulator of the microglial inflammatory response to plaques and that this inflammatory response can modulate Abeta deposition.