Growing evidence supports the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity [Tg(Dyrk1a), Ts65Dn, Dp1Yey], all expressing an extra copy of Dyrk1a. Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models. Brain functional magnetic resonance imaging reveals that this cognitive improvement is paralleled by functional connectivity remodelling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a quantitative phosphoproteomics method, revealing the implication of synaptic (synapsin 1) and cytoskeletal components involved in synaptic response and axonal organization. These results encourage the development of DYRK1A inhibitors as drug candidates to treat cognitive deficits associated with DS and AD.

Electron transfer (ET) kinetic rate constants k s in Ethaline (1:2 Choline Chloride + Ethylene Glycol) have been measured for two common redox couples (ferrocene/ferrocenium and ferrocyanide/ferricyanide) on a glassy carbon electrode and compared with ET kinetics in ionic liquids and classical organic solvents in the same conditions (acetonitrile and water). A particular care has been taken to treat ohmic drop in DES. For both couples, we found that ET rate constants are just a little lower than those measured in classical solvents (around 50% or less). These results contrast with ET rates in ionic liquids where electron transfers are considerably slower (100 times lower). Data are discussed as function of the solvent relaxation time using Marcus Theory for an adiabatic electron transfer.