Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer's disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25-35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ25-35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.
Conflict of interest statement
Organizations from whom the authors have received compensation for professional services: Guy Griebel, employee of Sanofi; Jeanne Stemmelin, employee of Sanofi; Mati Lopez-Grancha, employee of Sanofi; Denis Boulay, employee of Sanofi; Gérald Boquet, employee of Sanofi; Franck Slowinski, employee of Sanofi; Philippe Pichat, employee of Sanofi; Sandra Beeské, employee of Sanofi; Shinji Tanaka, employee of Mitsubishi Tanabe Pharma Corporation; Akiko Mori, employee of Mitsubishi Tanabe Pharma Corporation; Masatake Fujimura, employee of Mitsubishi Tanabe Pharma Corporation; Junichi Eguchi, employee of Mitsubishi Tanabe Pharma Corporation.
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