title: 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, 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 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.
authors.affiliation: Université Montpellier, INSERM U. 1198, place Eugène Bataillon, Montpellier Cedex 5 34095, France; Amylgen, 2196, boulevard de la Lironde, Montferrier-sur-Lez 34980, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Naert
authors.affiliation: Université Montpellier, INSERM U. 1198, place Eugène Bataillon, Montpellier Cedex 5 34095, France.
authors.forename: Valentine
authors.initials: V
authors.lastname: Ferré
authors.affiliation: Université Montpellier, INSERM U. 1198, place Eugène Bataillon, Montpellier Cedex 5 34095, France; Amylgen, 2196, boulevard de la Lironde, Montferrier-sur-Lez 34980, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Meunier
authors.affiliation: Université Montpellier, INSERM U. 1198, place Eugène Bataillon, Montpellier Cedex 5 34095, France; Amylgen, 2196, boulevard de la Lironde, Montferrier-sur-Lez 34980, France.
authors.forename: Emeline
authors.initials: E
authors.lastname: Keller
authors.affiliation: Université Montpellier, INSERM U. 1198, place Eugène Bataillon, Montpellier Cedex 5 34095, France; Amylgen, 2196, boulevard de la Lironde, Montferrier-sur-Lez 34980, France.
authors.forename: Susanna
authors.initials: S
authors.lastname: Malmström
authors.affiliation: Université Montpellier, INSERM U. 1198, place Eugène Bataillon, Montpellier Cedex 5 34095, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Givalois
authors.affiliation: Université Rennes, CNRS UMR 6226, Campus de Beaulieu, Bat. 10A, 10C, Avenue du Général Leclerc, Rennes Cedex 35042, France.
authors.forename: François
authors.initials: F
authors.lastname: Carreaux
authors.affiliation: Université Rennes, CNRS UMR 6226, Campus de Beaulieu, Bat. 10A, 10C, Avenue du Général Leclerc, Rennes Cedex 35042, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bazureau
authors.affiliation: Université Montpellier, INSERM U. 1198, place Eugène Bataillon, Montpellier Cedex 5 34095, France; Amylgen, 2196, boulevard de la Lironde, Montferrier-sur-Lez 34980, France. Electronic address: maurice@univ-montp2.fr.
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
mesh_terms: D016229:Amyloid beta-Peptides; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D016229:Amyloid beta-Peptides; D004149:Dioxoles; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007093:Imidazoles; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016875:tau Proteins; D000097603:Dyrk Kinases; C578491:((5Z)5-(1,3-benzodioxol-5-yl)methylene-2-phenylamino-3,5-dihydro-4H-imidazol-4-one); C558298:Mapt protein, mouse; C074636:amyloid beta-protein (25-35); C000605507:Gsk3b protein, mouse
keywords: Amyloid toxicity; Aβ(25–35); DYRK1A; Kinase; Leucettines; Tau phosphorylation