Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric A beta(25-35) peptide administration in mice

摘要

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) are implicated in the onset and progression of Down syndrome (DS) and Alzheimer's disease (AD). DYRK1A has emerged as a possible link between amyloid-beta (A beta) and Tau, the major pathological proteins in AD. We here assessed the neuroprotective potential of a novel inhibitor of DYRKs/CLKs. The Leucettine L41, acting preferentially on DYRK1A, was tested in A beta(25-35)-treated mice, a nontransgenic model of AD-like toxicity. We co-injected intracerebroventricularly oligomeric A beta(25-35) peptide and L41 in Swiss male mice. After 7 days, they were submitted to behavioral tests addressing spatial and non-spatial, short- and long-term memories. The oxidative stress, apoptotic markers, kinases involved in Tau phosphorylation, and synaptic integrity were analyzed by Western blot and ELISA in the hippocampus. L41, tested at 0.4, 1.2, 4 i.tg, prevented the A beta(25-35)-induced memory deficits in the Y-maze, passive avoidance and water-maze tests, with the most active dose being 4 lig. The inhibitor prevented the A beta(25-35) induced oxidative stress, as revealed by measures of lipid peroxidation levels and reactive oxygen species accumulation, and abolished A beta(25-35)-induced expression of pro-apoptotic markers. L41 prevented the A beta(25-35)-induced decrease of AKT activation and increase of glycogen synthase kinase-3 beta (GSK-3 beta) activation, resulting in a decrease of Tau phosphorylation. Finally, L41 restored A beta(25-35)-reduced levels of synaptic markers. The novel DYRK1A-preferential inhibitor L41 therefore prevented A beta(25-35)-induced memory impairments and neurotoxicity in the mouse hippocampus. These in vivo data highlighted particularly DYRK1A as a major kinase involved in A beta pathology and suggested therapeutic developments for DYRK1A inhibitors in AD. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.