title: Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans.
abstract: Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonin-dependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. cirritoj@neuro.wustl.edu
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.forename: Brianne M
authors.initials: BM
authors.lastname: Disabato
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Restivo
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Verges
authors.forename: Whitney D
authors.initials: WD
authors.lastname: Goebel
authors.forename: Anshul
authors.initials: A
authors.lastname: Sathyan
authors.forename: Davinder
authors.initials: D
authors.lastname: Hayreh
authors.forename: Gina
authors.initials: G
authors.lastname: D'Angelo
authors.forename: Tammie
authors.initials: T
authors.lastname: Benzinger
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yoon
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Mark A
authors.initials: MA
authors.lastname: Mintun
authors.forename: Yvette I
authors.initials: YI
authors.lastname: Sheline
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000814:Aniline Compounds / Q000008:administration & dosage; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D015283:Citalopram / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D049268:Positron-Emission Tomography; D011859:Radiography; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000008:administration & dosage; D013997:Time Factors
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D018687:Antidepressive Agents, Second-Generation; D013844:Thiazoles; D015283:Citalopram; D012701:Serotonin