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

Abstract：

: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.

journal_name

Aging Cell

journal_title

Aging cell

authors

Guglielmotto M,Monteleone D,Boido M,Piras A,Giliberto L,Borghi R,Vercelli A,Fornaro M,Tabaton M,Tamagno E

doi

10.1111/j.1474-9726.2012.00854.x

subject

Has Abstract

pub_date

2012-10-01 00:00:00

pages

834-44

issue

5

eissn

1474-9718

issn

1474-9726

journal_volume

11

pub_type

杂志文章

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