Dose-dependent improvements in learning and memory deficits in APPPS1-21 transgenic mice treated with the orally active Aβ toxicity inhibitor SEN1500

In the Alzheimer's disease (AD) brain, accumulation of A beta(1-42) peptides is suggested to initiate a cascade of pathological events. To date, no treatments are available that can reverse or delay AD-related symptoms in patients. In the current study, we introduce a new A beta toxicity inhibitor, SEN1500, which in addition to its block effect on A beta(1-42) toxicity in synaptophysin assays, can be administered orally and cross the blood brain barrier without adverse effects in mice. In a different set of animals, APPPS1-21 mice were fed with three different doses of SEN1500 (1 mg/kg, 5 mg/kg and 20 mg/kg) for a period of 5 months. Cognition was assessed in a variety of behavioral tests (Morris water maze, social recognition, conditioned taste aversion and passive avoidance). Results suggest a positive effect on cognition with 20 mg/kg SEN1500 compared to control APPPS1-21 mice. However, no changes in soluble or insoluble A beta(1-40) and A beta(1-42) were detected in the brains of SEN1500-fed mice. SEN1500 also attenuated the effect of A beta(1-42) on synaptophysin levels in mouse cortical neurons, which indicated that the compound blocked the synaptic toxicity of A beta(1-42). In vitro and in vivo effects presented here suggest that SEN1500 could be an interesting AD therapeutic. (C) 2013 Elsevier Ltd. All rights reserved.