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RESEARCH PRODUCT

Acitretin, an Enhancer of Alpha-Secretase Expression, Crosses the Blood-Brain Barrier and Is Not Eliminated by P-Glycoprotein

Florian SchuckUlrich SchmittKristina EndresChristoph HiemkeDavid HolthoewerFalk Fahrenholz

subject

MaleGenetically modified mouseATP Binding Cassette Transporter Subfamily BTime FactorsADAM10PharmacologyTransfectionAcitretinADAM10 ProteinMiceNeuroblastomachemistry.chemical_compoundCell Line TumormedicineAmyloid precursor proteinAnimalsHumansATP Binding Cassette Transporter Subfamily B Member 1Chromatography High Pressure LiquidP-glycoproteinMice KnockoutAnalysis of VarianceReporter genebiologyMembrane ProteinsMolecular biologyAcitretinADAM ProteinsGene Expression RegulationNeurologychemistryAlpha secretaseBlood-Brain Barrierbiology.proteinTamibaroteneNeurology (clinical)Amyloid Precursor Protein Secretasesmedicine.drug

description

<i>Background:</i> ADAM10 (a disintegrin and metalloproteinase 10) has been demonstrated to act as the main physiological α-secretase. Enzymatic activity of the α-secretase on the one hand prevents the formation of toxic Aβ peptides and on the other hand promotes the secretion of a neurotrophic and neuroprotective amyloid precursor protein fragment (APPs-α) by cleaving the amyloid precursor protein within its Aβ sequence. Enhancement of ADAM10’s gene expression may therefore present a valuable therapeutic approach for the treatment of Alzheimer’s disease (AD), where Aβ peptides are severely involved in the pathogenesis. <i>Objective:</i> In cell culture and in a transgenic mouse model of AD, retinoids led to increased ADAM10 expression and activity. We therefore endeavor to develop a clinical application of synthetic retinoids such as acitretin in AD. <i>Methods:</i> The effect of synthetic retinoids on ADAM10 gene expression was analyzed by reporter gene assays in human neuroblastoma cell line SH-SY5Y. Penetrance of acitretin into the murine brain was analyzed by high-performance liquid chromatography. P-glycoprotein (P-gp) double-knockout mice with a deficiency in both isoforms, mdr1a and 1b, were used to analyze a possible role of P-gp-dependent efflux on acitretin distribution. <i>Results:</i> Acitretin and tamibarotene are both potent activators of ADAM10 promoter activity. Acitretin crosses the murine blood-brain barrier and its level in the mouse brain is not reduced by P-gp. <i>Conclusion:</i> Synthetic retinoids and especially acitretin seem to be ideal candidates to establish an ADAM10-based AD treatment, and therefore have already entered first clinical trials.

https://doi.org/10.1159/000334300