Introduction: Translational 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.
Methods: We used a mouse model of Alzheimer's disease (APP/presenilin-1) to examine Posiphen's efficacy, pharmacodynamics, and pharmacokinetics.
Results: Posiphen 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.
Discussion: This is the first study demonstrating the therapeutic efficacy of inhibiting the translation of APP and its fragments in an Alzheimer's disease model.
Keywords: APP; APP/PS1; Alzheimer's disease; Aβ42; CTFα; CTFβ; Cognition; Long-term potentiation; Posiphen.