TRAF6 and p62 inhibit amyloid β-induced neuronal death through p75 neurotrophin receptor.

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 (p75NTR) and mediates Aβ-induced neuronal death. Recently, we showed that NGF leads to p75NTR polyubiquitination, which promotes neuronal cell survival. Here, we demonstrate that Aβ stimulation impaired the p75NTR polyubiquitination. TRAF6 and p62 are required for polyubiquitination of p75NTR on NGF stimulation. Interestingly, we found that overexpression of TRAF6/p62 restored p75NTR polyubiquitination upon Aβ/NGF treatment. Aβ significantly reduced NF-κB activity by attenuating the interaction of p75NTR with IKKβ. p75NTR 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 p75NTR polyubiquitination and restored neuronal cell survival.