title: Orally bioavailable small molecule drug protects memory in Alzheimer's disease models.
abstract: Oligomers of beta-amyloid (Aβ) are implicated in the early memory impairment seen in Alzheimer's disease before to the onset of discernable neurodegeneration. Here, the capacity of a novel orally bioavailable, central nervous system-penetrating small molecule 5-aryloxypyrimidine, SEN1500, to prevent cell-derived (7PA2 [conditioned medium] CM) Aβ-induced deficits in synaptic plasticity and learned behavior was assessed. Biochemically, SEN1500 bound to Aβ monomer and oligomers, produced a reduction in thioflavin-T fluorescence, and protected a neuronal cell line and primary cortical neurons exposed to synthetic soluble oligomeric Aβ(1-42). Electrophysiologically, SEN1500 alleviated the in vitro depression of long-term potentiation induced by both synthetic Aβ(1-42) and 7PA2 CM, and alleviated the in vivo depression of long-term potentiation induced by 7PA2 CM, after systemic administration. Behaviorally, oral administration of SEN1500 significantly reduced memory-related deficits in operant responding induced after intracerebroventricular injection of 7PA2 CM. SEN1500 reduced cytotoxicity, acute synaptotoxicity, and behavioral deterioration after in vitro and in vivo exposure to synthetic Aβ and 7PA2 CM, and shows promise for development as a clinically viable disease-modifying Alzheimer's disease treatment.
authors.affiliation: School of Psychology, Queen's University, Belfast BT7 1NN, UK. e.ohare@qub.ac.uk
authors.forename: Eugene
authors.initials: E
authors.lastname: O'Hare
authors.forename: David I C
authors.initials: DI
authors.lastname: Scopes
authors.forename: Eun-Mee
authors.initials: EM
authors.lastname: Kim
authors.forename: Philip
authors.initials: P
authors.lastname: Palmer
authors.forename: Martyn
authors.initials: M
authors.lastname: Jones
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Whyment
authors.forename: David
authors.initials: D
authors.lastname: Spanswick
authors.forename: Hozefa
authors.initials: H
authors.lastname: Amijee
authors.forename: Edmund
authors.initials: E
authors.lastname: Nerou
authors.forename: Bridgeen
authors.initials: B
authors.lastname: McMahon
authors.forename: J Mark
authors.initials: JM
authors.lastname: Treherne
authors.forename: Ross
authors.initials: R
authors.lastname: Jeggo
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D008297:Male; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D011743:Pyrimidines; C030986:pyrimidine