| First Author | Ledo JH | Year | 2016 |
| Journal | J Neurosci | Volume | 36 |
| Issue | 48 | Pages | 12106-12116 |
| PubMed ID | 27903721 | Mgi Jnum | J:237190 |
| Mgi Id | MGI:5811680 | Doi | 10.1523/JNEUROSCI.1269-16.2016 |
| Citation | Ledo JH, et al. (2016) Cross Talk Between Brain Innate Immunity and Serotonin Signaling Underlies Depressive-Like Behavior Induced by Alzheimer's Amyloid-beta Oligomers in Mice. J Neurosci 36(48):12106-12116 |
| abstractText | 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 Abeta oligomers (AbetaOs), 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 AbetaO-induced microglial activation, aberrant TNF-alpha signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNF-alpha and abolished depressive-like behavior induced by AbetaOs. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, AbetaOs 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 AbetaOs 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-beta oligomers (AbetaOs) 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 AbetaO-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. |
