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An antidepressant decreases CSF A? production in healthy individuals and in transgenic AD mice.

ABSTRACT: Serotonin signaling suppresses generation of amyloid-? (A?) 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 A? 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 A? production and A? concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram. A? 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 A? concentrations in the drug-treated group. The ability to safely decrease A? concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.

SUBMITTER: Sheline YI

PROVIDER: S-EPMC4269372 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Sheline Yvette I YI West Tim T Yarasheski Kevin K Swarm Robert R Jasielec Mateusz S MS Fisher Jonathan R JR Ficker Whitney D WD Yan Ping P Xiong Chengjie C Frederiksen Christine C Grzelak Monica V MV Chott Robert R Bateman Randall J RJ Morris John C JC Mintun Mark A MA Lee Jin-Moo JM Cirrito John R JR

Science translational medicine 20140501 236

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 pree ...[more]

PMID: 24828079

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Project description:BackgroundUnderstanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile.MethodsCross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [18F]-FDG, and [18F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex.ResultsThe prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2.ConclusionsThere are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials.Trial registrationNCT02485730.

Dataset Information

An antidepressant decreases CSF A? production in healthy individuals and in transgenic AD mice.

Publications

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

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