Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s DiseaseWalter S. · Letiembre M. · Liu Y. · Heine H. · Penke B. · Hao W. · Bode B. · Manietta N. · Walter J. · Schulz-Schüffer W. · Fassbender K.
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
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.
Dr. med. Silke Walter
Department of Neurology
University Hospital of the Saarland, Kirrbergerstr, 66421 Homburg (Germany)
Tel. + 49-6841-1624103, Fax: + 49-6841-1624137
Accepted: June 01, 2007
Number of Print Pages : 10
Cellular Physiology and Biochemistry (International Journal of Experimental Cellular Physiology, Biochemistry andPharmacology)
Vol. 20, No. 6, Year 2007 (Cover Date: 2007)
Journal Editor: F. Lang, Tübingen
ISSN: 1015–8987 (print), 1421–9778 (Online)
For additional information: http://www.karger.com/journals/cpb