Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease.
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.
Walter
Silke
S
Department of Neurology, University of the Saarland, Homburg, Germany. silke.walter@uniklinikum-saarland.de
Letiembre
Maryse
M
Liu
Yang
Y
Heine
Holger
H
Penke
Botond
B
Hao
Wenlin
W
Bode
Barbara
B
Manietta
Nicole
N
Walter
Jessica
J
Schulz-Schuffer
Walter
W
Fassbender
Klaus
K
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*
D016229:Amyloid beta-Peptides; C495377:LY96 protein, human; D018950:Lipopolysaccharide Receptors; D051218:Lymphocyte Antigen 96; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4