Regulation of secretases by all-trans retinoic acid

Koryakina, A. and Aeberhard, J. and Kiefer, S. and Hamburger, M. and Kueenzi, P.. (2009) Regulation of secretases by all-trans retinoic acid. FEBS Journal, 276 (9). pp. 2645-2655.

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Official URL: http://edoc.unibas.ch/dok/A5250902

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One of the emerging approaches for the treatment of Alzheimer's disease aims at reducing toxic levels of Alphabeta-species through the modulation of secretases, namely by inducing alpha-secretase or inhibiting beta-secretase and/or gamma-secretase activities, or a combination of both. Although there is increasing evidence for the involvement of retinoids in Alzheimer's disease, their significance in the regulation of Alphabeta-peptide production remains unresolved. Our work concentrated on the regulation of all secretases mediated by all-trans-retinoic acid (ATRA), and supports the hypothesis that ATRA is capable of regulating them in an antiamyloidogenic sense at the levels of transcription, translation, and activation. Apart from increased alpha-secretase activity, we show a complex chain of regulatory events, resulting in impaired beta-secretase trafficking and membrane localization upon protein kinase C (PKC) activation by ATRA. Furthermore, ATRA demonstrates substrate specificity for beta-site amyloid precursor protein-cleaving enzyme (BACE) 1 over nonamyloidogenic BACE2 in beta-secretase regulation, which probably promotes competition for amyloid precursor protein between ADAM17 and BACE1. Additionally, we report enhanced secretion of soluble amyloid precursor protein alpha after ATRA exposure, possibly due to PKC activation, as pretreatment with the PKC inhibitor Gö6976 abolished all these events.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Pharmazeutische Biologie (Hamburger)
UniBasel Contributors:Hamburger, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Nov 2017 10:56
Deposited On:22 Mar 2012 13:30

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