PMID- 17982277
OWN - NLM
STAT- MEDLINE
DCOM- 20071219
LR  - 20220408
IS  - 1015-8987 (Print)
IS  - 1015-8987 (Linking)
VI  - 20
IP  - 6
DP  - 2007
TI  - Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease.
PG  - 947-56
AB  - 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.
FAU - Walter, Silke
AU  - Walter S
AD  - Department of Neurology, University of the Saarland, Homburg, Germany. 
      silke.walter@uniklinikum-saarland.de
FAU - Letiembre, Maryse
AU  - Letiembre M
FAU - Liu, Yang
AU  - Liu Y
FAU - Heine, Holger
AU  - Heine H
FAU - Penke, Botond
AU  - Penke B
FAU - Hao, Wenlin
AU  - Hao W
FAU - Bode, Barbara
AU  - Bode B
FAU - Manietta, Nicole
AU  - Manietta N
FAU - Walter, Jessica
AU  - Walter J
FAU - Schulz-Schuffer, Walter
AU  - Schulz-Schuffer W
FAU - Fassbender, Klaus
AU  - Fassbender K
LA  - eng
PT  - Journal Article
PL  - Germany
TA  - Cell Physiol Biochem
JT  - Cellular physiology and biochemistry : international journal of experimental 
      cellular physiology, biochemistry, and pharmacology
JID - 9113221
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (LY96 protein, human)
RN  - 0 (Lipopolysaccharide Receptors)
RN  - 0 (Lymphocyte Antigen 96)
RN  - 0 (RNA, Messenger)
RN  - 0 (Toll-Like Receptor 4)
SB  - IM
MH  - Alzheimer Disease/*metabolism/*pathology
MH  - Amyloid beta-Peptides/pharmacology
MH  - Animals
MH  - Brain/drug effects/metabolism/pathology
MH  - Cell Line
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Inflammation/*metabolism/*pathology
MH  - Lipopolysaccharide Receptors/metabolism
MH  - Lymphocyte Antigen 96/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Microglia/drug effects/pathology
MH  - Monocytes/cytology/drug effects
MH  - Neurons/drug effects/*pathology
MH  - RNA, Messenger/genetics/metabolism
MH  - Toll-Like Receptor 4/genetics/*metabolism
EDAT- 2007/11/06 09:00
MHDA- 2007/12/20 09:00
CRDT- 2007/11/06 09:00
PHST- 2007/06/01 00:00 [accepted]
PHST- 2007/11/06 09:00 [pubmed]
PHST- 2007/12/20 09:00 [medline]
PHST- 2007/11/06 09:00 [entrez]
AID - 110455 [pii]
AID - 10.1159/000110455 [doi]
PST - ppublish
SO  - Cell Physiol Biochem. 2007;20(6):947-56. doi: 10.1159/000110455.