Late-onset Alzheimer’s disease is often connected with nutritional misbalance, such as enhanced cholesterol intake, deficiency in polyunsaturated fatty acids, or hypovitaminosis. The -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 -secretase activity by nonpermissive retinoid acid receptor/retinoid X receptor (RAR/RXR) heterodimers, whereby - and -isotypes of RAR play a major role. However, ligands of other RXR binding partners, such as the vitamin D receptor, do not stimulate -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 EC₅₀ of 1.5 µM and led to an increase of mature ADAM10 protein that resulted in a two- to three-fold increase of the ratio between - and -secretase activity in neuroblastoma cells. The -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 A₄₀ and A₄₂. 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 -secretase ADAM10 by retinoic acid receptors and acitretin.