Correction of cognitive deficits in mouse models of Down syndrome by pharmacological inhibitor of DYRK1A

Down Syndrome (DS) results from the trisomy of human chromosome 21 (HSA21). It is still the most frequent intellectual disability, affecting 1 newborn per 700 births. Among candidate genes explaining intellectual disabilities seen in DS patients, the dual specificity tyrosine-phosphorylation regulated kinase 1A, DYRK1A, is located in the DS critical region of chromosome 21. DYRK1A has become a major screening target for the development of selective and potent pharmacological inhibitors. We here investigated the effects of a relatively selective DYRK1A inhibitor, Leucettine 41 (hereafter L41) in three different trisomic mouse models with increasing genetic complexity, Tg(Dyrk1a), Ts65Dn and Dp1Yey. Leucettines are derived from the marine sponge alkaloid Leucettamine B.