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

Sep 19, 2015European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology

Leucettine L41 may prevent memory loss and brain damage caused by amyloid beta peptide in mice

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Abstract

L41, tested at 4 µg, prevented Aβ25-35-induced memory deficits in mice.

The inhibitor L41 acted preferentially on DYRK1A and was effective in a nontransgenic mouse model of Alzheimer's-like toxicity.
L41 prevented oxidative stress induced by Aβ25-35, as indicated by reduced lipid peroxidation and reactive oxygen species accumulation.
The treatment abolished the expression of pro-apoptotic markers caused by Aβ25-35 exposure.
L41 maintained AKT activation and reduced glycogen synthase kinase-3β activation, leading to decreased Tau phosphorylation.
The inhibitor restored levels of synaptic markers diminished by Aβ25-35.

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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.

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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

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