Aβ1-42-mediated down-regulation of Uch-L1 is dependent on NF-κB activation and impaired BACE1 lysosomal degradation.
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.
Department of Experimental Medicine and Oncology, University of Torino, Torino, Italy.
Michela
M
Guglielmotto
Debora
D
Monteleone
Marina
M
Boido
Antonio
A
Piras
Luca
L
Giliberto
Roberta
R
Borghi
Alessandro
A
Vercelli
Michele
M
Fornaro
Massimo
M
Tabaton
Elena
E
Tamagno
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D008247:Lysosomes; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D010446:Peptide Fragments; C482860:UCHL1 protein, human; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D043222:Ubiquitin Thiolesterase; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human