Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse - PubMed (original) (raw)
doi: 10.1016/j.trci.2017.12.001. eCollection 2018.
Ekta Sharma 2, Eliza Barnwell 2, Hong Zhang 1, Agnieszka Staniszewski 1, Tadanobu Utsuki 2, Vasudevaraju Padmaraju 2, Cheryl Mazell 2, Apostolia Tzekou 3, Kumar Sambamurti 2, Ottavio Arancio 1, Maria L Maccecchini 3
Affiliations
- PMID: 29955650
- PMCID: PMC6021259
- DOI: 10.1016/j.trci.2017.12.001
Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse
Andrew F Teich et al. Alzheimers Dement (N Y). 2018.
Abstract
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.
Figures
Fig. 1
Posiphen rescues defects in spatial memory of APP/PS1 mice. (A) Daily oral treatment with 25 mg/kg, but not 10 mg/kg, Posiphen starting from 2 months of age for 1 month reduced the number of errors that the APP/PS1 mice made in the 2-day RAWM test, in comparison to saline-treated transgenic mice [WT vehicle vs. APP/PS1 vehicle: F (1, 33) = 4.9, P = .0339; APP/PS1 vehicle vs. APP/PS1 Posiphen 10 mg/kg: F (1, 34) = 1.4, P = .2453; and APP/PS1 vehicle vs. APP/PS1 Posiphen 25 mg/kg: F (1, 35) = 5.13, P = .0298]. WT mice were not affected by 25 mg/kg Posiphen treatment [WT vehicle vs. WT Posiphen 25 mg/kg: F (1, 34) = 0.16, P = .6887]. (B and C) All treatment groups shown in (A) displayed similar speed (B) and latency (C) to a visible platform above the water surface. Mean and SEM are shown. N = 17–19 per group. Abbreviations: APP, amyloid precursor protein; PS1, presenilin-1; RAWM, radial arm water maze; SEM, standard error of the mean; WT, wild-type.
Fig. 2
Posiphen rescues the defect in associative memory of APP/PS1 mice. (A) Daily oral treatment of APP/PS1 mice with either 10 or 25 mg/kg Posiphen starting at 2 months of age for 1 month reestablished normal freezing in a test for contextual fear memory, in comparison to saline-treated APP/PS1 mice (t tests for 24-hour contextual: WT vehicle vs. APP/PS1 vehicle, P < .0001; APP/PS1 vehicle vs. APP/PS1 Posiphen 10 mg/kg, P = .005; and APP/PS1 vehicle vs. APP/PS1 Posiphen 25 mg/kg, P = .0185). WT mice were not affected by Posiphen treatment (t test WT vehicle vs. WT Posiphen 25 mg/kg, P = .5304). Freezing (%) was comparable for all groups at baseline. (B and C) Daily oral treatment with Posiphen starting at 2 months of age for 1 month in the animals shown in (A) did not affect cued memory (B) and capability of mice to perceive the electric shock (C) in neither WT nor APP/PS1 mice, as compared to saline-treated controls. Mean and SEM are shown. N = 17–19 per group. Abbreviations: APP, amyloid precursor protein; PS1, presenilin-1; SEM, standard error of the mean; WT, wild-type.
Fig. 3
Daily oral treatment with Posiphen starting at 2 months of age for 1.5 months reestablished normal potentiation in slices derived from APP/PS1 mice, as compared to saline-treated controls [WT vehicle vs. APP/PS1 vehicle: F (1, 14) = 60.54, P < .0001; APP/PS1 vehicle vs. APP/PS1 Posiphen 10 mg/kg: F (1, 15) = 10.72, P = .0051; and APP/PS1 vehicle vs. APP/PS1 Posiphen 25 mg/kg: F (1, 15) = 54.22, P < .0001]. WT mice were not affected by Posiphen treatment [WT vehicle vs. WT Posiphen 25 mg/kg: F (1, 14) = 0.7477, P = .4018]. Mean and SEM are shown. N = 8–9 per group. Abbreviations: APP, amyloid precursor protein; fEPSP, field excitatory postsynaptic potential; PS1, presenilin-1; SEM, standard error of the mean; WT, wild-type.
Fig. 4
Distribution of Posiphen and its metabolites in plasma and brain of APP/PS1 mice. Concentration of Posiphen and its main metabolites in plasma and brain of mice treated with 25 mg/kg p.o. for 2 weeks (A) or 75 mg/kg IP for 1 week, followed by 50 mg/kg IP for 2 weeks (B) was determined by LC-MS/MS. N8-norPosiphen is the most abundant form, while all molecules are found mostly in the brain. The brain:plasma ratio of Posiphen, N1-norPosiphen, and N8-norPosiphen is roughly 8, 7, and 7, respectively in case of (A) and 6, 4, and 3, respectively in case of (B). Mean and SEM are shown. N = 3 per group. Abbreviations: APP, amyloid precursor protein; PS1, presenilin-1; p.o., per os; IP, intraperitoneal; SEM, standard error of the mean.
Fig. 5
Effect of daily oral treatment with 25 mg/kg Posiphen (P) (starting at 2 months of age for 1.5 months) on APP levels in the hippocampus of APP/PS1 mice, as compared to vehicle (V, saline). Representative APP Western blot and plotted APP relative densitometric units are presented. A 21% decrease of APP expression was observed in the hippocampus of Posiphen-treated mice in comparison to vehicle-treated controls, although the difference was not statistically significant (t test, P = .186). Mean and SEM are shown. N = 7/group. Abbreviations: APP, amyloid precursor protein; PS1, presenilin-1; SEM, standard error of the mean.
Fig. 6
Posiphen treatment of APP/PS1 transgenic mice produces a prolonged decrease in biomarker levels in the hippocampus. Mice were treated IP with saline (control group) or Posiphen at 75 mg/kg for 1 week and 50 mg/kg for 2 weeks. The mice were euthanized in batches of five at 1.5, 3, 6 and 9 hours after the final Posiphen treatment. The seventh in a series of 1-mm thick coronal brain slices was used to compare the levels of APP (A), CTFβ (B), CTFα (C) by Western blots, and Aβ42 (D) and Aβ40 (E) by ELISA. No trend for recovery of biomarker levels is observed up to 9 hours. Relative densitometric units are presented for (A–C). Mean and SEM are shown. N = 5 per group. (F) Representative example of Western blots for APP, CTFβ, and CTFα. An NSB indicates equal protein loading. (G) The data corresponding to all time points after the last Posiphen dose were averaged and used to calculate the percentage of reduction in expression levels of biomarkers or Western blot loading controls (GAPDH and synaptophysin) after Posiphen treatment, in comparison to the control group (=100%). The expression levels at all time points after Posiphen treatment versus control group were compared by one-way ANOVA, resulting in the listed P values. Abbreviations: Aβ, amyloid β; ANOVA, analysis of variance; APP, amyloid precursor protein; CTF, carboxy-terminal fragment; ELISA, enzyme-linked immunosorbent assay; IP, intraperitoneal; NSB, nonspecific band; PS1, presenilin-1; SEM, standard error of the mean.
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