Aβ1‐42‐mediated down‐regulation of Uch‐L1 is dependent on NF‐κB activation and impaired BACE1 lysosomal degradation

Summary Amyloid‐β 1‐42 accumulation is the major pathogenetic event in Alzheimer’s disease (AD), believed to be responsible for synaptic dysfunction and neuronal cell death. However, the physiologic activity of Aβ peptides remains elusive: Aβ might not only play a toxic role, but also act as a functional signaling intermediate. We recently reported that Aβ1‐42 promotes BACE1 transcription through the activation of the JNK‐c‐jun pathway. Here, we show that the Aβ1‐42‐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 NT 2 neuronal cells. We also found that the increase in BACE1 and the decrease in Uch‐L1 are related events and depend on NF‐κB pathway; thus, Aβ1‐42 is able to activate NF‐κB 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 Aβ1‐42 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.