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

• Published in: Neuropharmacology 2013-12, Vol.75, p.458-466
• Main Authors: Lo, Adrian C., Tesseur, Ina, Scopes, David I.C., Nerou, Edmund, Callaerts-Vegh, Zsuzsanna, Vermaercke, Ben, Treherne, J. Mark, De Strooper, Bart, D'Hooge, Rudi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alzheimer Disease - complications; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Protein Precursor - genetics; Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Aniline Compounds - therapeutic use; Animals; APPPS1-21; Avoidance Learning - drug effects; Aβ toxicity inhibitor; Disease Models, Animal; Gene Expression Regulation - drug effects; Humans; Learning Disorders - drug therapy; Learning Disorders - etiology; Maze Learning - drug effects; Memory Disorders - etiology; Mice; Mice, Transgenic; Morris water maze; Mutation - genetics; Nitriles - administration & dosage; Nitriles - chemistry; Peptide Fragments - antagonists & inhibitors; Presenilin-1 - genetics; Pyrimidines - administration & dosage; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; SEN1500; Synaptophysin - metabolism; Taste - drug effects
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.08.030

In the Alzheimer's disease (AD) brain, accumulation of Aβ1–42 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 Aβ toxicity inhibitor, SEN1500, which in addition to its block effect on Aβ1–42 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 Aβ1–40 and Aβ1–42 were detected in the brains of SEN1500-fed mice. SEN1500 also attenuated the effect of Aβ1–42 on synaptophysin levels in mouse cortical neurons, which indicated that the compound blocked the synaptic toxicity of Aβ1–42. In vitro and in vivo effects presented here suggest that SEN1500 could be an interesting AD therapeutic. •Introduction of new active Abeta toxicity inhibitor.•First demonstration in an in vivo AD mouse model.•Different behavioral tasks show converging results.•Dose-dependent improvement of learning and memory.•SEN1500 blocks Aβ1–42 toxicity in synaptophysin assays.