Open AccessTranslational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse
Author(s) -
Teich Andrew F.,
Sharma Ekta,
Barnwell Eliza,
Zhang Hong,
Staniszewski Agnieszka,
Utsuki Tadanobu,
Padmaraju Vasudevaraju,
Mazell Cheryl,
Tzekou Apostolia,
Sambamurti Kumar,
Arancio Ottavio,
Maccecchini Maria L.
Publication year - 2018
Publication title -
alzheimer's and dementia: translational research and clinical interventions
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.49
H-Index - 30
ISSN - 2352-8737
DOI - 10.1016/j.trci.2017.12.001
Subject(s) - presenilin , pharmacodynamics , amyloid precursor protein , pharmacology , pharmacokinetics , disease , medicine , translation (biology) , neuroscience , alzheimer's disease , psychology , chemistry , biochemistry , messenger rna , gene
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 N 8 ‐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.