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LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide

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Cherny,  D. I.
Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society;

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Citation

Liu, Y., Walter, S., Stagi, M., Cherny, D. I., Letiembre, M., Schulz-Schaeffer, W., et al. (2005). LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain, 128(8): doi:10.1093/brain/awh531, pp. 1778-1789. Retrieved from http://brain.oxfordjournals.org/cgi/content/full/128/8/1778.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0012-E962-0
Abstract
The amyloid β peptide 42 (Aβ₄₂) plays a key role in neurotoxicity in Alzheimer’s disease. Mononuclear phagocytes, i.e. microglia, have the potential to clear Aβ 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 Aβ₄₂ 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 Aβ₄₂ 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 Aβ₄₂ added to cultured primary microglial cells was phagocytosed into the cytoplasmic compartment in a CD14-dependent manner. This phagocytosis occurred at Aβ₄₂ 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 Aβ₄₂, demonstrating a direct role of CD14 in Aβ₄₂ 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.