Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric Aβ25–35 peptide administration in mice

Abstract

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-β (Aβ) 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 Aβ25–35-treated mice, a nontransgenic model of AD-like toxicity. We co-injected intracerebroventricularly oligomeric Aβ25–35 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, 4µg, prevented the Aβ25–35-induced memory deficits in the Y-maze, passive avoidance and water-maze tests, with the most active dose being 4µg. The inhibitor prevented the Aβ25–35-induced oxidative stress, as revealed by measures of lipid peroxidation levels and reactive oxygen species accumulation, and abolished Aβ25–35-induced expression of pro-apoptotic markers. L41 prevented the Aβ25–35-induced decrease of AKT activation and increase of glycogen synthase kinase-3β (GSK-3β) activation, resulting in a decrease of Tau phosphorylation. Finally, L41 restored Aβ25–35-reduced levels of synaptic markers. The novel DYRK1A-preferential inhibitor L41 therefore prevented Aβ25–35-induced memory impairments and neurotoxicity in the mouse hippocampus. These in vivo data highlighted particularly DYRK1A as a major kinase involved in Aβ pathology and suggested therapeutic developments for DYRK1A inhibitors in AD.