An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice.
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.
Departments of Psychiatry, Radiology, and Neurology, University of Pennsylvania, Philadelphia , PA 19104, USA. sheline@mail.med.upenn.edu.
Yvette I
YI
Sheline
C2N Diagnostics LLC, St. Louis, MO 63110, USA.
Tim
T
West
Department of Medicine, Washington University, St. Louis, MO 63110, USA.
Kevin
K
Yarasheski
Department of Anesthesiology, Washington University, St. Louis, MO 63110, USA.
Robert
R
Swarm
Department of Biostatistics, Washington University, St. Louis, MO 63110, USA.
Mateusz S
MS
Jasielec
Department of Neurology, Washington University, St. Louis, MO 63110, USA.
Jonathan R
JR
Fisher
Department of Neurology, Washington University, St. Louis, MO 63110, USA.
Whitney D
WD
Ficker
Department of Neurology, Washington University, St. Louis, MO 63110, USA.
Ping
P
Yan
Department of Biostatistics, Washington University, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University Medical Center, St. Louis, MO 63110, USA.
Chengjie
C
Xiong
Department of Surgery, Washington University, St. Louis, MO 63110, USA.
Christine
C
Frederiksen
Department of Neurology, Washington University, St. Louis, MO 63110, USA.
Monica V
MV
Grzelak
Department of Medicine, Washington University, St. Louis, MO 63110, USA.
Robert
R
Chott
Department of Neurology, Washington University, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University Medical Center, St. Louis, MO 63110, USA. Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA.
Randall J
RJ
Bateman
Department of Neurology, Washington University, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University Medical Center, St. Louis, MO 63110, USA.
John C
JC
Morris
Avid Radiopharmaceuticals and Eli Lilly Inc., Philadelphia, PA 19104, USA.
Mark A
MA
Mintun
Department of Neurology, Washington University, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University Medical Center, St. Louis, MO 63110, USA. Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA.
Jin-Moo
JM
Lee
Department of Neurology, Washington University, St. Louis, MO 63110, USA. Knight Alzheimer's Disease Research Center, Washington University Medical Center, St. Louis, MO 63110, USA. Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA.
John R
JR
Cirrito
D000328:Adult; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid*; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry*; D001921:Brain / Q000378:metabolism; D015283:Citalopram / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D017551:Microdialysis; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000378:metabolism; D011446:Prospective Studies; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry; D015398:Signal Transduction; D055815:Young Adult
D016564:Amyloid beta-Protein Precursor; D000928:Antidepressive Agents; D015283:Citalopram; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors