Journal Article

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

Yang Liu, Silke Walter, Massimiliano Stagi, Dmitry Cherny, Maryse Letiembre, Walter Schulz-Schaeffer, Holger Heine, Botond Penke, Harald Neumann and Klaus Fassbender

in Brain

Published on behalf of The Guarantors of Brain

Volume 128, issue 8, pages 1778-1789
Published in print August 2005 | ISSN: 0006-8950
Published online August 2005 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awh531
LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide

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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.

Keywords: Alzheimer's disease; amyloid β protein; CD14; microglia; phagocytosis; Aβ = amyloid β peptide; CHO = Chinese hamster ovary; fAβ42 = fibrillar amyloid β 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-α = tumour necrosis factor-α

Journal Article.  7467 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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