title: Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease.
abstract: 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, TNFalpha 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.
authors.affiliation: Department of Neurology, University of the Saarland, Homburg, Germany. silke.walter@uniklinikum-saarland.de
authors.forename: Silke
authors.initials: S
authors.lastname: Walter
authors.forename: Maryse
authors.initials: M
authors.lastname: Letiembre
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Holger
authors.initials: H
authors.lastname: Heine
authors.forename: Botond
authors.initials: B
authors.lastname: Penke
authors.forename: Wenlin
authors.initials: W
authors.lastname: Hao
authors.forename: Barbara
authors.initials: B
authors.lastname: Bode
authors.forename: Nicole
authors.initials: N
authors.lastname: Manietta
authors.forename: Jessica
authors.initials: J
authors.lastname: Walter
authors.forename: Walter
authors.initials: W
authors.lastname: Schulz-Schuffer
authors.forename: Klaus
authors.initials: K
authors.lastname: Fassbender
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C495377:LY96 protein, human; D018950:Lipopolysaccharide Receptors; D051218:Lymphocyte Antigen 96; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4