PMID- 26109305
OWN - NLM
STAT- MEDLINE
DCOM- 20150910
LR  - 20190318
IS  - 0371-0874 (Print)
IS  - 0371-0874 (Linking)
VI  - 67
IP  - 3
DP  - 2015 Jun 25
TI  - The role of the TLR4/NF-kappaB signaling pathway in Abeta accumulation in primary 
      hippocampal neurons.
PG  - 319-28
AB  - The present study aimed to investigate the role of the Toll-like receptor 4 
      (TLR4)/nuclear factor kappaB (NF-kappaB) signaling pathway in the accumulation of amyloid 
      beta protein (Abeta) in primary hippocampal neurons of rats. The purity of these 
      cultured neurons was determined by using immunofluorescence techniques. 
      Lipopolysaccharide (LPS, a TLR4 ligand) or CLI-095 (a TLR4 inhibitor) was used to 
      activate or inhibit TLR4 signaling, respectively. Pyrrolidine dithiocarbamate 
      (PDTC), on the other hand, was used to inhibit NF-kappaB, a downstream effector of 
      the TLR4 signaling pathway. The contents of tumor necrosis factor-alpha (TNF-alpha), 
      interleukin-1beta (IL-1beta) and Abeta1-42 in the supernatant were assessed by 
      enzyme-linked immunosorbent assay (ELISA). The mRNA levels of TNF-alpha, IL-1beta, a 
      disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), beta-site 
      APP cleaving enzyme 1 (BACE-1), Presenilin-1 (PS-1), and beta-amyloid precursor 
      protein (beta-APP) were examined by real-time quantitative PCR (RT-qPCR). The 
      protein levels of ADAM10, BACE-1, PS-1 and beta-APP were examined by Western 
      blotting. Meanwhile, the levels of TLR4 mRNA and protein in hippocampal neurons 
      were tested by RT-qPCR and Western blotting, respectively, after stimulation with 
      Abeta1-42 at different concentrations. We observed that the purity of cultured 
      hippocampal neurons after being cultured for 7 days was above 95%. Compared with 
      untreated neurons, LPS-treated neurons showed higher expression levels of TNF-alpha, 
      IL-1beta, BACE-1, PS-1, beta-APP, and Abeta1-42, but a lower expression level of ADAM10. 
      These effects were reversed upon pre-treatment with CLI-095 or PDTC. Furthermore, 
      TLR4 expression was upregulated in the presence of Abeta1-42. Taken together, these 
      results provide evidence that elevation in the level of inflammatory cytokines 
      accompanies the activation of TLR4 signaling, and that the consequent 
      downregulation of ADAM10 and upregulation of BACE-1/PS-1 are likely responsible 
      for the accumulation of beta-APP and Abeta, which in turn increases TLR4 level to 
      create a positive feedback loop that may constitute the basis for the progression 
      of Alzheimer's disease.
FAU - Wu, Dan
AU  - Wu D
AD  - Department of Pathophysiology, Medical School of Nantong University, Nantong 
      226001, China.
AD  - Department of Neurology, Affiliated Hospital of Nantong University, Nantong 
      226001, China.
FAU - Zhang, Xian
AU  - Zhang X
AD  - Department of Infectious Disease, Affiliated Hospital of Nantong University, 
      Nantong 226001, China.
FAU - Zhao, Min
AU  - Zhao M
AD  - Department of Pathology, Nantong Tumour Hospital, Nantong 226001, China.
FAU - Zhou, Ai-Ling
AU  - Zhou AL
AD  - Department of Pathophysiology, Medical School of Nantong University, Nantong 
      226001, China. ALZ@ntu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - China
TA  - Sheng Li Xue Bao
JT  - Sheng li xue bao : [Acta physiologica Sinica]
JID - 20730130R
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Peptide Fragments)
RN  - 0 (RNA, Messenger)
RN  - 0 (Sulfonamides)
RN  - 0 (Tlr4 protein, rat)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (amyloid beta-protein (1-42))
RN  - 0 (ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate)
SB  - IM
MH  - Alzheimer Disease
MH  - Amyloid beta-Peptides/*metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Hippocampus/cytology
MH  - Interleukin-1beta/metabolism
MH  - Lipopolysaccharides
MH  - NF-kappa B/*metabolism
MH  - Neurons/*metabolism
MH  - Peptide Fragments/metabolism
MH  - RNA, Messenger
MH  - Rats
MH  - *Signal Transduction
MH  - Sulfonamides
MH  - Toll-Like Receptor 4/*metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
EDAT- 2015/06/26 06:00
MHDA- 2015/09/12 06:00
CRDT- 2015/06/26 06:00
PHST- 2015/06/26 06:00 [entrez]
PHST- 2015/06/26 06:00 [pubmed]
PHST- 2015/09/12 06:00 [medline]
PST - ppublish
SO  - Sheng Li Xue Bao. 2015 Jun 25;67(3):319-28.