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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 pathol. 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, 4 μg, prevented the Aβ25-35-induced memory deficits in the Y-maze, passive avoidance and water-maze tests, with the most active dose being 4 μg. The inhibitor prevented the Aβ25-35-induced oxidative stress, as revealed by measures of lipid peroxidn. 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 pathol. and suggested therapeutic developments for DYRK1A inhibitors in AD. [on SciFinder(R)]
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01146496
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Submitted on : Tuesday, June 16, 2015 - 1:29:29 PM
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Gaëlle Naert, Valentine Ferré, Johann Meunier, Emeline Keller, Susanna Malmstrom, et al.. Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric Aβ25-35 peptide administration in mice.. European Neuropsychopharmacology, Elsevier, 2015, 25 (11), pp.2170-2182. ⟨10.1016/j.euroneuro.2015.03.018⟩. ⟨hal-01146496⟩

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