PT  - JOURNAL ARTICLE
AU  - Jose Henrique Ledo
AU  - Estefania P. Azevedo
AU  - Danielle Beckman
AU  - Felipe C. Ribeiro
AU  - Luis E. Santos
AU  - Daniela S. Razolli
AU  - Grasielle C. Kincheski
AU  - Helen M. Melo
AU  - Maria Bellio
AU  - Antonio L. Teixeira
AU  - Licio A. Velloso
AU  - Debora Foguel
AU  - Fernanda G. De Felice
AU  - Sergio T. Ferreira
TI  - Cross Talk Between Brain Innate Immunity and Serotonin Signaling Underlies Depressive-Like Behavior Induced by Alzheimer's Amyloid-β Oligomers in Mice
AID  - 10.1523/JNEUROSCI.1269-16.2016
DP  - 2016 Nov 30
TA  - The Journal of Neuroscience
PG  - 12106--12116
VI  - 36
IP  - 48
4099  - http://www.jneurosci.org/content/36/48/12106.short
4100  - http://www.jneurosci.org/content/36/48/12106.full
SO  - J. Neurosci.2016 Nov 30; 36
AB  - 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 Aβ oligomers (AβOs), 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 AβO-induced microglial activation, aberrant TNF-α signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNF-α and abolished depressive-like behavior induced by AβOs. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, AβOs 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 AβOs 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.SIGNIFICANCE STATEMENT Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia in the world. Brain accumulation of amyloid-β oligomers (AβOs) is a major feature in the pathogenesis of AD. Although clinical and epidemiological data suggest a strong connection between AD and depression, the underlying mechanisms linking these two disorders remain largely unknown. Here, we report that aberrant activation of the brain innate immunity and decreased serotonergic tonus in the brain are key players in AβO-induced depressive-like behavior in mice. Our findings may open up new possibilities for the development of effective therapeutics for AD and depression aimed at modulating microglial function.