tailieunhanh - Báo cáo khoa học: Regulation of secretases by all-trans-retinoic acid

One of the emerging approaches for the treatment of Alzheimer’s disease aims at reducing toxic levels of Ab-species through the modulation of secretases, namely by inducing a-secretase or inhibiting b-secretase and⁄or c-secretase activities, or a combination of both. | ỊFEBS Journal Regulation of secretases by all-trans-retinoic acid Anna Koryakina Jessica Aeberhard Sabine Kiefer Matthias Hamburger and Peter Kuenzi Institute of PharmaceuticalBiology University of Basel Switzerland Keywords Alzheimer s disease PDBu phorbol-12 13-dibutyrate PKC protein kinase C retinoic acid secretases Correspondence P. Kuenzi Institute of Pharmaceutical Biology University of Basel Klingelbergstrasse 50 4056 Basel Switzerland Fax 41 61 267 14 74 Tel 41 61 267 15 44 E-mail Received 12 January 2009 revised 19 February 2009 accepted 4 March 2009 doi One of the emerging approaches for the treatment of Alzheimer s disease aims at reducing toxic levels of Ab-species through the modulation of secretases namely by inducing a-secretase or inhibiting b-secretase and or y-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 Ab-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 a-secretase activity we show a complex chain of regulatory events resulting in impaired b-secretase trafficking and membrane localization upon protein kinase C PKC activation by ATRA. Furthermore ATRA demonstrates substrate specificity for b-site amyloid precursor protein-cleaving enzyme BACE 1 over nonamyloidogenic BACE2 in b-secretase regulation which probably promotes competition for amyloid precursor protein between ADAM17 and BACE1. Additionally we report enhanced secretion of soluble amyloid precursor protein a after ATRA exposure possibly due to PKC activation as pretreatment with the PKC inhibitor Go6976 abolished all these events. The .