Brain Advance Access first published online on April 27, 2005
This version published online on May 11, 2005
Brain, doi:10.1093/brain/awh531
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1 Departments of Neurology, University of Göttingen, Göttingen, Germany
* To whom correspondence should be addressed. The amyloid
Article
LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide
2 Department of Neurology, University of Göttingen, Göttingen, Germany
3 European Neuroscience Institute, University of Göttingen and Hertie-Foundation, Göttingen, Germany; Institute of Multiple Sclerosis Research, University of Göttingen and Hertie-Foundation, Göttingen, Germany
4 Department of Biochemistry, University of Leicester, Leicester, UK; Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia
5 Department of Neuropathology, University of Göttingen, Göttingen, Germany
6 Borstel Research Centre, Centre for Medicine and Biosciences, Borstel, Germany
7 Department of Medical Chemistry, Albert Szent Gyorgyi Medical University, Szeged, Hungary
8 Department of Neurology, University Hospital, Homburg, Saar, Germany
Yang Liu, E-mail: alexliu{at}med.uni-goettingen.de
Abstract 
peptide 42 (A42) plays a key role in neurotoxicity in Alzheimer's disease. Mononuclear phagocytes, i.e. microglia, have the potential to clear A by phagocytosis. Recently, the lipopolysaccharide (LPS) receptor CD14 was shown to mediate phagocytosis of bacterial components and furthermore to contribute to neuroinflammation in Alzheimer's disease. Here, we investigated whether this key innate immunity receptor can interact with A42 and mediate phagocytosis of this peptide. Using flow cytometry, confocal microscopy and two-photon fluorescence lifetime imaging (FLIM) combined with fluorescence resonance energy transfer (FRET), we demonstrated a direct molecular interaction in the range of a few nanometers between A42 and CD14 in human CD14-transfected Chinese hamster ovary cells. Investigations using cells that were genetically deficient for this receptor showed that in <30 minutes exogenous A42 added to cultured primary microglial cells was phagocytosed into the cytoplasmic compartment in a CD14-dependent manner. This phagocytosis occurred at A42 concentration ranges that were considerably lower than the threshold to activate a cellular inflammatory reaction. In contrast, there was no association of CD14 to microglial internalization of microbeads. In complementary clinical experiments, we detected a pronounced CD14 immunoreactivity on parenchymal microglia spatially correlated to characteristic Alzheimer's disease lesion sites in brain sections of Alzheimer's disease patients but not in brain sections of control subjects. By showing a close interaction between CD14 and A42, demonstrating a direct role of CD14 in A42 phagocytosis, and detecting CD14-specific staining in brains of Alzheimer's disease patients, our results indicate a role of the LPS receptor in the pathophysiology of Alzheimer's disease, which could be of therapeutic relevance. protein; CD14; microglia; phagocytosis.
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