Abstract
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.
Highlights
Neuropsychiatric symptoms (NPS) are frequently observed in patients with Alzheimer’s disease (AD) and are being increasingly recognized as hallmarks of this condition and related dementias[1]
glycogen synthase kinase-3 (GSK3) which was discovered about 30 years ago is a serine/threonine protein kinase involved in a variety of cellular processes, e.g., microtubule dynamics, gene transcription and cell proliferation[4,5,6]
Evidence supporting the idea that GSK3 inhibitors may have an additional potential for alleviating neuropsychiatric symptoms (NPS) originates from several studies in animals showing that GSK3 inhibition may contribute to the action of antidepressants[13,14,15,16,17] and antipsychotics[18,19,20,21,22,23]
Summary
Neuropsychiatric symptoms (NPS) are frequently observed in patients with Alzheimer’s disease (AD) and are being increasingly recognized as hallmarks of this condition and related dementias[1]. GSK3 is involved in AD progression, including pathophysiological formation of paired helical filament tau, an integral part of the deposits of neurofibrillary tangle responsible for disruption of neuronal function in this condition[7] Inhibiting this protein kinase has been suggested to be a potential strategy to treat patients suffering from AD (see[8,9] for two recent reviews). Evidence supporting a therapeutic potential of these molecules in other NPS, such as anxiety or agitation has not been well established In this context, the objective of this study was to characterize the behavioral effects of the selective ATP competitive GSK3 inhibitor, SAR502250 (a.k.a. UDA-680) (Fig. 1), in models related to certain aspects of NPS, including agitation, aggression, anxiety, cognitive and sensorimotor deficits, and depression.
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