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Up‐regulation of the α‐secretase ADAM10 by retinoic acid receptors and acitretin
Author(s) -
Tippmann Frank,
Hundt Jana,
Schneider Anja,
Endres Kristina,
Fahrenholz Falk
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-121392
Subject(s) - adam10 , retinoid , acitretin , retinoid x receptor , retinoic acid , endocrinology , chemistry , medicine , receptor , retinoid x receptor alpha , bexarotene , biology , pharmacology , biochemistry , immunology , psoriasis , nuclear receptor , gene , metalloproteinase , enzyme , disintegrin , transcription factor
Late‐onset Alzheimer's disease is often connected with nutritional misbalance, such as enhanced cholesterol intake, deficiency in polyunsaturated fatty acids, or hypovitaminosis. The α‐secretase ADAM10 has been found to be regulated by retinoic acid, the bioreactive metabolite of vitamin A. Here we show that retinoids induce gene expression of ADAM10 and α‐secretase activity by nonpermissive retinoid acid receptor/retinoid X receptor (RAR/RXR) heterodimers, whereby α‐and β‐isotypes of RAR play a major role. However, ligands of other RXR binding partners, such as the vitamin D receptor, do not stimulate β‐secretase activity. On the basis of these findings, we examined the effect of synthetic retinoids and found a strong enhancement of nonamyloidogenic processing of the amyloid precursor protein by the vitamin A analog acitretin: it stimulated ADAM10 promoter activity with an EC 50 of 1.5 μ.M and led to an increase of mature ADAM10 protein that resulted in a two‐to three‐fold increase of the ratio between α‐and β‐secretase activity in neuroblastoma cells. The α‐secretase stimulation by acitretin was completely inhibited by the ADAM10‐specific inhibitor GI254023X. Intracerebral injection of acitretin in APP/PS1‐21 transgenic mice led to a reduction of Aβ 40 and Aβ 42 . The results of this study may have clinical relevance because acitretin has been approved for the treatment of psoriasis since 1997 and found generally safe for long‐term use in humans.—Tippmann, F.,Hundt, J., Schneider, A., Endres, K., Fahrenholz, F. Up‐regulation of the α‐secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 23, 1643–1654 (2009)