Cross talk between brain innate immunity and serotonin signaling underlies depressive-like behavior induced by Alzheimer’s amyloid-β oligomers in mice

Jose Henrique Ledo, Estefania P. Azevedo, Danielle Beckman, Felipe C. Ribeiro, Luis E. Santos, Daniela S. Razolli, Grasielle C. Kincheski, Helen M. Melo, Maria Bellio, Antonio L. Teixeira, Licio A. Velloso, Debora Foguel, Fernanda G. De Felice, Sergio T. Ferreira

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

Abstract

Considerable clinical and epidemiological evidence links Alzheimer’s disease (AD) and depression. However, the molecular mechanisms underlying this connection are largely unknown. We reported recently that soluble A÷ oligomers (A÷Os), toxins that accumulate in AD brains and are thought to instigate synapse damage and memory loss, induce depressive-like behavior in mice. Here, we report that the mechanism underlying this action involves A÷O-induced microglial activation, aberrant TNF-signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNF- and abolished depressive-like behavior induced by A÷Os. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, A÷Os failed to induce depressive-like behavior in Toll-like receptor 4-deficient mice and in mice harboring a nonfunctional TLR4 variant in myeloid cells. Results establish that A÷Os trigger depressive-like behavior via a double impact on brain serotonin levels and microglial activation, unveiling a cross talk between brain innate immunity and serotonergic signaling as a key player in mood alterations in AD.

Original languageEnglish (US)
Pages (from-to)12106-12116
Number of pages11
JournalJournal of Neuroscience
Volume36
Issue number48
DOIs
StatePublished - Nov 30 2016
Externally publishedYes

Keywords

  • Alzheimer’s
  • Depression
  • Inflammation
  • Microglia
  • Serotonin

ASJC Scopus subject areas

  • General Neuroscience

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