Beta-amyloid binds to p57NTR and activates NFkappaB in human neuroblastoma cells.
Amyloid beta peptide (Abeta), a proteolytic fragment of the amyloid precursor protein (APP), is a major component of the plaques found in the brain of Alzheimer's disease (AD) patients. These plaques are thought to cause the observed loss of cholinergic neurons in the basal forebrain of AD patients. In these neurons, particularly those of the nucleus basalis of Meynert, an up-regulation of 75kD-neurotrophin receptor (p75NTR), a nonselective neurotrophin receptor belonging to the death receptor family, has been reported. p75NTR expression has been described to correlate with beta-amyloid sensitivity in vivo and in vitro, suggesting a possible role for p75NTR as a receptor for Abeta. Here we used a human neuroblastoma cell line to investigate the involvement of p75NTR in Abeta-induced cell death. Abeta peptides were found to bind to p75NTR resulting in activation of NFKB in a time- and dose-dependent manner. Blocking the interaction of Abeta with p75NTR using NGF or inhibition of NFKB activation by curcumin or NFKB SN50 attenuated or abolished Abeta-induced apoptotic cell death. The present results suggest that p75NTR might be a death receptor for Abeta, thus being a possible drug target for treatment of AD.
Kuner
P
P
F. Hoffmann-LaRoche AG, Pharma Division Preclinical Research, Basel, Switzerland.
Schubenel
R
R
Hertel
C
C
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D003474:Curcumin / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009447:Neuroblastoma; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D003474:Curcumin