Andrew F. Teich1, Ekta Sharma2, Eliza Barnwell2, Hong Zhang1, Agnieszka Staniszewski1, Tadanobu Utsuki2, Vasudevaraju Padmaraju2, Cheryl Mazell2, Apostolia Tzekou3, Kumar Sambamurti2, Ottavio Arancio1, Maria L. Maccecchini3
1Department of Pathology and Cell Biology, Taub Institute, Columbia University, New York City, NY, USA
2Department of Neurosciences and Ophthalmology, Medical University of South Carolina, Charleston, SC, USA
3QR Pharma Inc., Berwyn, PA, USA
Tóm tắt
AbstractIntroductionTranslational inhibition of amyloid precursor protein (APP) by Posiphen has been shown to reduce APP and its fragments in cell culture, animal models, and mildly cognitively impaired patients, making it a promising drug candidate for the treatment of Alzheimer's disease.MethodsWe used a mouse model of Alzheimer's disease (APP/presenilin‐1) to examine Posiphen's efficacy, pharmacodynamics, and pharmacokinetics.ResultsPosiphen treatment normalized impairments in spatial working memory, contextual fear learning, and synaptic function in APP/presenilin‐1 mice, without affecting their visual acuity, motor skills, or motivation and without affecting wild‐type mice. Posiphen had a prolonged effect in reducing APP and all related peptides for at least 9 hours after the last dose. Its concentration was higher in the brain than in plasma, and the most abundant metabolite was N8‐norPosiphen.DiscussionThis is the first study demonstrating the therapeutic efficacy of inhibiting the translation of APP and its fragments in an Alzheimer's disease model.
