LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide.
The amyloid beta peptide 42 (Abeta(42)) plays a key role in neurotoxicity in Alzheimer's disease. Mononuclear phagocytes, i.e. microglia, have the potential to clear Abeta 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 Abeta(42) 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 Abeta(42) 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 Abeta(42) added to cultured primary microglial cells was phagocytosed into the cytoplasmic compartment in a CD14-dependent manner. This phagocytosis occurred at Abeta(42) 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 Abeta(42), demonstrating a direct role of CD14 in Abeta(42) 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.
Liu
Yang
Y
Department of Neurology, University of Göttingen, Germany. alexliu@med.uni-goettingen.de
Walter
Silke
S
Stagi
Massimiliano
M
Cherny
Dmitry
D
Letiembre
Maryse
M
Schulz-Schaeffer
Walter
W
Heine
Holger
H
Penke
Botond
B
Neumann
Harald
H
Fassbender
Klaus
K
D000544:Alzheimer Disease / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D019921:Biotinylation; D001921:Brain / Q000276:immunology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology; D018613:Microscopy, Confocal / Q000379:methods; D010587:Phagocytosis / Q000276:immunology*; D016133:Polymerase Chain Reaction / Q000379:methods; D014158:Transcription, Genetic
D016229:Amyloid beta-Peptides; D018950:Lipopolysaccharide Receptors