ABSTRACT
Amyloid ß (Aß) aggregates are the primary component of senile plaques in Alzheimer disease (AD) patient's brain. Aß is known to bind p75 neurotrophin receptor (p75(NTR)) and mediates Aß-induced neuronal death. Recently, we showed that NGF leads to p75(NTR) polyubiquitination, which promotes neuronal cell survival. Here, we demonstrate that Aß 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 Aß/NGF treatment. Aß significantly reduced NF-κB activity by attenuating the interaction of p75(NTR) with IKKß. p75(NTR) increased NF-κB activity by recruiting TRAF6/p62, which thereby mediated cell survival. These findings indicate that TRAF6/p62 abrogated the Aß-mediated inhibition of p75(NTR) polyubiquitination and restored neuronal cell survival.
