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ID: 218712.0, MPI für biophysikalische Chemie / Molekulare Biologie (Dr. Thomas M. Jovin)
LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide
Authors:Liu, Y.; Walter, S.; Stagi, M.; Cherny, D. I.; Letiembre, M.; Schulz-Schaeffer, W.; Heine, H.; Penke, B.; Neumann, H.; Fassbender, K.
Language:English
Date of Publication (YYYY-MM-DD):2005-04-27
Title of Journal:Brain
Volume:128
Issue / Number:8
Start Page:1778
End Page:1789
Sequence Number of Article:doi:10.1093/brain/awh531
Review Status:not specified
Audience:Not Specified
Intended Educational Use:No
Abstract / Description: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.
Free Keywords:Alzheimer’s disease; amyloid β protein; CD14; microglia; phagocytosis
Last Change of the Resource (YYYY-MM-DD):2005-08-31
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für biophysikalische Chemie/Abt. Thomas Jovin / 060
External Affiliations:Department of Neurology, University Hospital, Hamburg; Department of Neuropathology, University of Göttingen; European Neuroscience Institute and Institute of Multiple Sclerosis Research, University of Göttingen and Hertie-Foundation, Göttingen; Borstel Research Centre, Centre for Medicine and Biosciences, Borstel, Germany; Department of Biochemistry, University of Leicester, Leicester, UK; Institute of Molecular Genetics, Russian Academy
of Sciences, Moscow, Russia;Department of Medical Chemistry, Albert Szent Gyorgyi Medical University, Szeged, Hungary
Identifiers:URL:http://brain.oxfordjournals.org/cgi/content/full/1...
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