The Journal of Neuroscience, September 23, 2009, 29(38):11982-11992; doi:10.1523/JNEUROSCI.3158-09.2009
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Neurobiology of Disease
CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation
Erin G. Reed-Geaghan,1
Julie C. Savage,1
Amy G. Hise,2 and
Gary E. Landreth1
1Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, and 2Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio 44106
Correspondence should be addressed to Gary E. Landreth, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4928. Email: gel2{at}case.edu
Microglia are the brain's tissue macrophages and are found in an activated state surrounding β-amyloid plaques in the Alzheimer's disease brain. Microglia interact with fibrillar β-amyloid (fAβ) through an ensemble of surface receptors composed of the 
6β1 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 report that the response of microglial cells to fibrillar forms of Aβ requires the participation of Toll-like receptors (TLRs) and the coreceptor CD14. The response of microglia to fAβ is reliant upon CD14, which act together with TLR4 and TLR2 to bind fAβ and to activate intracellular signaling. We find that cells lacking these receptors could not initiate a Src-Vav-Rac signaling cascade leading to reactive oxygen species production and phagocytosis. The fAβ-mediated activation of p38 MAPK also required CD14, TLR4, and TLR2. Inhibition of p38 abrogated fAβ-induced reactive oxygen species production and attenuated the induction of phagocytosis. Microglia lacking CD14, TLR4, and TLR2 showed no induction of phosphorylated I
B following fAβ. These data indicate these innate immune receptors function as members of the microglial fAβ receptor complex and identify the signaling mechanisms whereby they contribute to microglial activation.
Received July 2, 2009;
revised Aug. 18, 2009;
accepted Aug. 19, 2009.
Correspondence should be addressed to Gary E. Landreth, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4928. Email: gel2{at}case.edu
