Serotonin signaling is associated with lower amyloid-βlevels and plaques in transgenic mice and humans

John R. Cirrito, Brianne M. Disabato, Jessica L. Restivo, Deborah K. Verges, Whitney D. Goebel, Anshul Sathyan, Davinder Hayreh, Gina D'Angelo, Tammie Benzinger, Hyejin Yoon, Jungsu Kim, John C. Morris, Mark A. Mintun, Yvette I. Sheline

Research output: Contribution to journalArticle

170 Scopus citations

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 Aβlevels 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. Serotonindependent 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.

Original languageEnglish (US)
Pages (from-to)14968-14973
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number36
DOIs
StatePublished - Sep 6 2011

Keywords

  • Late-life depression
  • Microdialysis
  • Selective serotonin reuptake inhibitor antidepressants

ASJC Scopus subject areas

  • General

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    Cirrito, J. R., Disabato, B. M., Restivo, J. L., Verges, D. K., Goebel, W. D., Sathyan, A., Hayreh, D., D'Angelo, G., Benzinger, T., Yoon, H., Kim, J., Morris, J. C., Mintun, M. A., & Sheline, Y. I. (2011). Serotonin signaling is associated with lower amyloid-βlevels and plaques in transgenic mice and humans. Proceedings of the National Academy of Sciences of the United States of America, 108(36), 14968-14973. https://doi.org/10.1073/pnas.1107411108