Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse

Abstract

IntroductionTranslational 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.

Early-Occurring Dendritic Spines Alterations in Mouse Models of Alzheimer’s Disease Inform on Primary Causes of Neurodegeneration

“…Confirming that upregulation of translation contributes to AD pathogenesis, pharmacological (salubrinal) restoration of proper translational control in early symptomatic 3-month-old Tg2576 mice reverts structural and functional alterations including spine loss and prevalent LTD at CA1 hippocampal synapses, downregulates their increased levels of the β-secretase enzyme BACE-1, one main determinant of amyloidogenic APP processing, and prevents the manifestation of cognitive alterations (Borreca et al, 2020 ). Consistent with these findings, compounds like MMP13 (Zhu et al, 2019 ), which regulates BACE-1 translation, or posiphen, which decreases the production of toxic Aβ by lowering APP translation, are effective in rescuing cognitive deficits in hAPP mutant mice (Lahiri et al, 2007 ) and sporadic AD patients (Teich et al, 2018 ). Together, these data suggest that the dysregulation of APP cleavage whose Aβo formation and spines deterioration are the earliest manifestations could largely depend on the abnormal amount of full-length APP to be cleaved at early stages of development.…”

Iron in Neurodegeneration – Cause or Consequence?

“…Posiphen potently inhibits translation of APP and α-synuclein in preclinical models (Shaw et al, 2001; Yu et al, 2013; Teich et al, 2018). In a phase I human trial and a small non-randomized study of five subjects with mild cognitive impairment, administration of posiphen is well tolerated and decreases levels of sAPPα, sAPPβ, total and phosphorylated tau, and inflammatory marker in CSF.…”

Exploring the Pathogenesis of Alzheimer Disease in Basal Forebrain Cholinergic Neurons: Converging Insights From Alternative Hypotheses

“…Alternatively, small molecules that interfere with translation of APP mRNA may prove useful. Posiphen is one such molecule; it reduced the levels of APP and its products, including Aβ42, in a translation-dependent manner in AD mouse models (Lahiri et al, 2007; Teich et al, 2018). In studies on a small number of MCI patients, treatment with Posiphen for 10 days reduced in CSF the secreted amino terminal fragments of APP (i.e., sAPPα and sAPPβ), total tau, p-tau, and showed a trend toward reduced Aβ42 (Maccecchini et al, 2012).…”