title: TRAF6 and p62 inhibit amyloid β-induced neuronal death through p75 neurotrophin receptor.
abstract: Amyloid β (Aβ) aggregates are the primary component of senile plaques in Alzheimer disease (AD) patient's brain. Aβ is known to bind p75 neurotrophin receptor (p75(NTR)) and mediates Aβ-induced neuronal death. Recently, we showed that NGF leads to p75(NTR) polyubiquitination, which promotes neuronal cell survival. Here, we demonstrate that Aβ stimulation impaired the p75(NTR) polyubiquitination. TRAF6 and p62 are required for polyubiquitination of p75(NTR) on NGF stimulation. Interestingly, we found that overexpression of TRAF6/p62 restored p75(NTR) polyubiquitination upon Aβ/NGF treatment. Aβ significantly reduced NF-κB activity by attenuating the interaction of p75(NTR) with IKKβ. p75(NTR) increased NF-κB activity by recruiting TRAF6/p62, which thereby mediated cell survival. These findings indicate that TRAF6/p62 abrogated the Aβ-mediated inhibition of p75(NTR) polyubiquitination and restored neuronal cell survival.
authors.affiliation: Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA.
authors.forename: Thangiah
authors.initials: T
authors.lastname: Geetha
authors.forename: Chen
authors.initials: C
authors.lastname: Zheng
authors.forename: Wade C
authors.initials: WC
authors.lastname: McGregor
authors.forename: B
authors.initials: B
authors.lastname: Douglas White
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Jeganathan Ramesh
authors.initials: JR
authors.lastname: Babu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D016373:DNA, Antisense / Q000235:genetics; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D011499:Protein Processing, Post-Translational; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D017384:Sequence Deletion; D000071456:Sequestosome-1 Protein; D048029:TNF Receptor-Associated Factor 6 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016373:DNA, Antisense; D006360:Heat-Shock Proteins; D016328:NF-kappa B; D010446:Peptide Fragments; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D048029:TNF Receptor-Associated Factor 6; C517634:Ngfr protein, mouse; C078592:amyloid beta-protein (1-40); D020932:Nerve Growth Factor