Brain Advance Access originally published online on April 27, 2005
Brain 2005 128(8):1778-1789; doi:10.1093/brain/awh531
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LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide
1 Departments of Neurology and 2 Neuropathology, University of Göttingen, 3 European Neuroscience Institute and 4 Institute of Multiple Sclerosis Research, University of Göttingen and Hertie-Foundation, Göttingen, 5 Borstel Research Centre, Centre for Medicine and Biosciences, Borstel, 6 Department of Neurology, University Hospital, Homburg, Saar, Germany, 7 Department of Biochemistry, University of Leicester, Leicester, UK, 8 Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia and 9 Department of Medical Chemistry, Albert Szent Gyorgyi Medical University, Szeged, Hungary
Correspondence to: Yang Liu or Klaus Fassbender, Department of Neurology, University of Göttingen, Robert Koch Str. 40, 37075 Göttingen, Germany E-mail: alexliu{at}med.uni-goettingen.de; klaus.fassbender{at}med.uni-goettingen.de
The amyloid ß peptide 42 (Aß42) plays a key role in neurotoxicity in Alzheimer's disease. Mononuclear phagocytes, i.e. microglia, have the potential to clear Aß 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 Aß42 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 Aß42 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 Aß42 added to cultured primary microglial cells was phagocytosed into the cytoplasmic compartment in a CD14-dependent manner. This phagocytosis occurred at Aß42 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 Aß42, demonstrating a direct role of CD14 in Aß42 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.
Key Words: Alzheimer's disease; amyloid ß protein; CD14; microglia; phagocytosis
Abbreviations:
Aß = amyloid ß peptide; CHO = Chinese hamster ovary; fAß42 = fibrillar amyloid ß peptide 42; FLIM = fluorescence lifetime imaging; FRET = fluorescence resonance energy transfer; iNOS = inducible nitric oxide synthase; LPS = lipopolysaccharide; mFI = mean fluorescence value; SEM = standard error of the mean; TCSPC = time-correlated single photon counting; TNF-
= tumour necrosis factor-
.
* These authors contributed equally to this work.
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