title: Dose-dependent improvements in learning and memory deficits in APPPS1-21 transgenic mice treated with the orally active Aβ toxicity inhibitor SEN1500.
abstract: 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.
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Belgium; Leuven Institute for Neuroscience & Disease (LIND), Belgium.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Lo
authors.affiliation: Center for Human Genetics, University of Leuven, Belgium; VIB Center for the Biology of Disease, VIB, Leuven, Belgium; Leuven Institute for Neuroscience & Disease (LIND), Belgium.
authors.forename: Ina
authors.initials: I
authors.lastname: Tesseur
authors.affiliation: Senexis Limited, Babraham Research Campus, Cambridge, United Kingdom.
authors.forename: David I C
authors.initials: DI
authors.lastname: Scopes
authors.affiliation: Senexis Limited, Babraham Research Campus, Cambridge, United Kingdom.
authors.forename: Edmund
authors.initials: E
authors.lastname: Nerou
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Belgium; Leuven Institute for Neuroscience & Disease (LIND), Belgium.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Callaerts-Vegh
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Belgium; Leuven Institute for Neuroscience & Disease (LIND), Belgium.
authors.forename: Ben
authors.initials: B
authors.lastname: Vermaercke
authors.affiliation: Senexis Limited, Babraham Research Campus, Cambridge, United Kingdom.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Treherne
authors.affiliation: Center for Human Genetics, University of Leuven, Belgium; VIB Center for the Biology of Disease, VIB, Leuven, Belgium; Leuven Institute for Neuroscience & Disease (LIND), Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Belgium; Leuven Institute for Neuroscience & Disease (LIND), Belgium. Electronic address: rudi.dhooge@ppw.kuleuven.be.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007859:Learning Disabilities / Q000188:drug therapy* / Q000209:etiology*; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009570:Nitriles / Q000008:administration & dosage* / Q000737:chemistry; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D053764:Presenilin-1 / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016708:Synaptophysin / Q000378:metabolism; D013649:Taste / Q000187:drug effects
chemical_list: C000590687:2-fluoro-5-(5-(3-morpholin-4-ylphenoxy)pyrimidin-2-ylamino)benzonitrile; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; D009570:Nitriles; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D011743:Pyrimidines; D016708:Synaptophysin; C075222:amyloid beta-protein (1-42); C014356:benzonitrile
keywords: APPPS1-21; Alzheimer's disease; Aβ toxicity inhibitor; Morris water maze; SEN1500