CHIP stabilizes amyloid precursor protein via proteasomal degradation and p53‐mediated trans‐repression of β‐secretase

Summary In patient with Alzheimer's disease ( AD ), deposition of amyloid‐beta Aβ, a proteolytic cleavage of amyloid precursor protein ( APP ) by β‐secretase/ BACE 1, forms senile plaque in the brain. BACE 1 activation is caused due to oxidative stresses and dysfunction of ubiquitin–proteasome system ( UPS ), which is linked to p53 inactivation. As partial suppression of BACE 1 attenuates Aβ generation and AD ‐related pathology, it might be an ideal target for AD treatment. We have shown that both in neurons and in HEK ‐ APP cells, BACE 1 is a new substrate of E3‐ligase CHIP and an inverse relation exists between CHIP and BACE 1 level. CHIP inhibits ectopic BACE 1 level by promoting its ubiquitination and proteasomal degradation, thus reducing APP processing; it stabilizes APP in neurons, thus reducing Aβ. CHIP U box domain physically interacts with BACE 1; however, both U‐box and TPR domain are essential for ubiquitination and degradation of BACE 1. Further, BACE 1 is a downstream target of p53 and overexpression of p53 decreases BACE 1 level. In HEK ‐ APP cells, CHIP is shown to negatively regulate BACE 1 promoter through stabilization of p53's DNA ‐binding conformation and its binding upon 5′ UTR element (+127 to +150). We have thus discovered that CHIP regulates p53‐mediated trans‐repression of BACE 1 at both transcriptional and post‐translational level. We propose that a CHIP – BACE 1–p53 feedback loop might control APP stabilization, which could further be utilized for new therapeutic intervention in AD .