Aß1-42-mediated down-regulation of Uch-L1 is dependent on NF-?B activation and impaired BACE1 lysosomal degradation

Amyloid-beta 1-42 accumulation is the major pathogenetic event in Alzheimers disease (AD), believed to be responsible for synaptic dysfunction and neuronal cell death. However, the physiologic activity of A beta peptides remains elusive: A beta might not only play a toxic role, but also act as a functional signaling intermediate. We recently reported that A beta 1-42 promotes BACE1 transcription through the activation of the JNK-c-jun pathway. Here, we show that the A beta 1-42-mediated increase in BACE1 expression is accompanied by a decrease in ubiquitin C-terminal hydrolase L1 (Uch-L1) expression and activity in different cellular models such as neuroblastoma SH-SY5Y as well as NT2 neuronal cells. We also found that the increase in BACE1 and the decrease in Uch-L1 are related events and depend on NF-?B pathway; thus, A beta 1-42 is able to activate NF-?B pathway and the pretreatment with a pharmacological inhibitor, able to block the nuclear translocation of the transactivating unit p65, almost completely prevents both the decrease in Uch-L1 and the increase in BACE1 expression. In addition, the decrease in Uch-L1 activity interferes with the lysosomal degradation of BACE1, as demonstrated by the decrease in Cathepsin D activity and the partial accumulation of BACE1 in lysosomes after A beta 1-42 treatment as well after Uch-L1 inhibition. In support of the in vitro data, we observed low protein levels of Uch-L1 associated with high protein levels of BACE1 in sporadic AD brains. Our data suggest that Uch-L1 could be an attractive target for the development of new therapeutic approaches for AD.