An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice

Abstract

Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer's disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor, decreased Aβ in brain interstitial fluid in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of preexisting plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram's effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.

Fig. 1. Citalopram reduces ISF Aβ concentrations in aged APP/PS1 mice

(A) 12 month old APP/PS1 mice were implanted with microdialysis probes in the hippocampus. Baseline ISF Aβ was established over 8 hours followed by administration of vehicle (PBS) or citalopram (2.5, 5, 10, 20 mg/kg ip). ISF Aβ was sampled every 90 minutes. A repeated measures ANOVA demonstrated a treatment effect of ***p <0.0001. N=5 per group. (B) The mean concentration of ISF Aβ_x-40 at hours 21–24 after drug administration was 103%, 105.8%, 87.6%, 75.5%, and 72.5% (mean % ± SE 3.56) for vehicle and ascending doses of citalopram, respectively, compared to baseline in each mouse. There was a significant reduction in ISF Aβ at 5, 10 and 20 mg/kg citalopram compared to vehicle-treated mice (p=0.003, p<0.0001, and p<0.0001, respectively). Aβ concentrations after 10 mg/kg citalopram were significantly lower than for 5 mg/kg (p=0.02) but did not differ significantly from the 20 mg/kg dose.

Fig. 2. Citalopram reduces amyloid plaque formation and growth in APP/PS1 mice

Six month-old APP/PS1 mice were treated with Citalopram 10mg/kg per day or vehicle i.p. for 28d (Vehicle: n=6 mice, 49 plaques; Citalopram: n=8 mice, 116 plaques) and imaged using 2 photon microscopy. (A) Representative multiphoton micrographs of individual amyloid plaques in the cortex of APP/PS1 mice before (0d) and 28 days after treatment. A repeated measures ANOVA indicated that Citalopram attenuated the growth of pre-existing plaques. P: plaque; CAA: cerebral amyloid angiopathy; New P: newly appearing plaque. (B) Analysis using a cumulative logit model demonstrated that Citalopram reduced the likelihood of plaque growth, but did not induce plaque regression (C) Citalopram also reduced the appearance of new plaques based on comparison using a Wilcoxon rank-sum test (D), and inhibited CAA progression, based on a comparison using a t-test (E) during the 28 days of treatment compared to vehicle control. Scale bar, 50 μM; *P < 0.05; ** P < 0.01, ***P<0.001, **** P < 0.001 for Odds Ratio. Values represent mean ± SE.

Fig. 3. Citalopram reduces CSF Aβ concentrations and production rate in healthy human volunteers

(A) Comparison of hourly CSF Aβ concentrations over 37 hours of sampling in healthy human volunteers treated with citalopram or placebo. (B) Using repeated measures ANOVA, subjects who received citalopram had lower mean CSF concentrations of Aβ (31.4 +/− 0.64) ng/mL over hours 8–45 compared with placebo (50.3+/− 0.99) ng/mL (p=0.001). (C) Newly generated Aβ is decreased following administration of citalopram compared with placebo, determined from incorporation of 13C-Leucine; 13C-Leucine is not radioactive but the different isotope can be detected by mass spectrometry. (D) The mean production rate of Aβ over hours 13–22 was significantly slower in citalopram-treated individuals [1.33 (0.16) versus 2.11 (0.20) ng/ml/hr, p=0.005], but the clearance rate of Aβ was unchanged [−0.61 (0.14) versus −0.96 (0.16) ng/ml/hr, p=0.115]. Values represent mean and 95% CI (A, C) and mean ± SE (B, D) and p-values are based on repeated measures ANOVA derived approximate t-tests.