Abstract:
:Dysregulation of beta-site APP-cleaving enzyme (BACE) and/or gamma-secretase leads to anomalous production of amyloid-beta peptide (Abeta) and contributes to the etiology of Alzheimer's disease (AD). Since these secretases mediate proteolytic processing of numerous proteins, little success has been achieved to treat AD by secretase inhibitors because of inevitable undesired side effects. Thus, it is of importance to unravel the regulatory mechanisms of these secretases. Here, we show that delta-opioid receptor (DOR) promotes the processing of Abeta precursor protein (APP) by BACE1 and gamma-secretase, but not that of Notch, N-cadherin or APLP. Further investigation reveals that DOR forms a complex with BACE1 and gamma-secretase, and activation of DOR mediates the co-endocytic sorting of the secretases/receptor complex for APP endoproteolysis. Dysfunction of the receptor retards the endocytosis of BACE1 and gamma-secretase and thus the production of Abeta. Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Abeta pathology and Abeta-dependent behavioral deficits, but does not affect the processing of Notch, N-cadherin or APLP in AD model mice. Our study not only uncovers a molecular mechanism for the formation of a DOR/secretase complex that regulates the specificity of secretase for Abeta production but also suggests that intervention of either formation or trafficking of the GPCR/secretase complex could lead to a new strategy against AD, potentially with fewer side effects.
journal_name
Cell Resjournal_title
Cell researchauthors
Teng L,Zhao J,Wang F,Ma L,Pei Gdoi
10.1038/cr.2010.3subject
Has Abstractpub_date
2010-02-01 00:00:00pages
138-53issue
2eissn
1001-0602issn
1748-7838pii
cr20103journal_volume
20pub_type
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