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Original Paper

Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s Disease

Walter S.1 · Letiembre M.1 · Liu Y.1 · Heine H.2 · Penke B.3 · Hao W.1 · Bode B.4 · Manietta N.1 · Walter J.1 · Schulz-Schüffer W.5 · Fassbender K.1

Author affiliations

1Department of Neurology, University of the Saarland, Homburg, Germany,2Borstel Research Center, Center for Medicine and Biosciences, Borstel, Germany,3Department of Medical Chemistry, Albert Szent Gyorgyi University, Szeged, Hungary,4Department of Neurology, Ludwigshafen Hospital, Germany5Department of Neuropathology, University of Goettingen, Germany

Corresponding Author

Dr. med. Silke Walter

Department of Neurology

University Hospital of the Saarland, Kirrbergerstr, 66421 Homburg (Germany)

Tel. + 49-6841-1624103, Fax: + 49-6841-1624137

E-Mail silke.walter@uniklinikum-saarland.de

Related Articles for ""

Cell Physiol Biochem 2007;20:947–956

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Microglial activation is a key feature in Alzheimer’s disease and is considered to contribute to progressive neuronal injury by release of neurotoxic products. The innate immune receptor Toll-like-receptor 4 (TLR4), localized on the surface of microglia, is a first-line host defense receptor against invading microorganisms. Here, we show that a spontaneous loss-of-function mutation in the Tlr4 gene strongly inhibits microglial and monocytic activation by aggregated Alzheimer amyloid peptide resulting in a significantly lower release of the inflammatory products IL-6, TNFα and nitric oxide. Treatment of primary murine neuronal cells with supernatant of amyloid peptide-stimulated microglia demonstrates that Tlr4 contributes to amyloid peptide-induced microglial neurotoxicity. In addition, stimulation experiments in transfected HEK293 cells allowed to define a tri-molecular receptor complex consisting of TLR4, MD-2 and CD14 necessary for full cellular activation by aggregated amyloid peptide. A clinical relevance of these findings is supported by a marked upregulation of Tlr4 mRNA in APP transgenic mice and by an increased expression of TLR4 in Alzheimer’s disease brain tissue associated with amyloid plaque deposition. Together, these observations provide the first evidence for a role of the key innate immune receptor, TLR4, in neuroinflammation in Alzheimer’s disease.

© 2007 S. Karger AG, Basel

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Published online: October 30, 2007
Issue release date: October 2007

Number of Print Pages: 10
Number of Figures: 0
Number of Tables: 0

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

For additional information: http://www.karger.com/CPB

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