TRAF6 and p62 inhibit amyloid β-induced neuronal death through p75 neurotrophin receptor
Amyloid Î² (AÎ²) aggregates are the primary component of senile plaques in Alzheimer disease (AD) patient’s brain. AÎ² is known to bind p75 neurotrophin receptor (p75NTR) and mediates AÎ²-induced neuronal death. Recently, we showed that NGF leads to p75NTR polyubiquitination, which promotes neuronal cell survival. Here, we demonstrate that AÎ² 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 AÎ²/NGF treatment. AÎ² significantly reduced NF-ÎºB activity by attenuating the interaction of p75NTR with IKKÎ². p75NTR Increased NF-ÎºB activity by recruiting TRAF6/p62, which thereby mediated cell survival. These findings indicate that TRAF6/p62 abrogated the AÎ²-mediated inhibition of p75NTR polyubiquitination and restored neuronal cell survival. âº AÎ² treatment impairs p75NTR polyubiquitination and its interaction with TRAF6/p62. âº AÎ² attenuates the NF-ÎºB activation and neuronal cell survival induced by NGF. âº Overexpression of TRAF6/p62 restores p75NTR ubiquitination and neuronal survival. âº p75NTR Ubiquitination may serve as biomarkers for neurodegeneration.