Cross Talk Between Brain Innate Immunity and Serotonin Signaling Underlies Depressive-Like Behavior Induced by Alzheimer's Amyloid-β Oligomers in Mice

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 beta oligomers (A beta 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 beta O-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 A beta Os. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, A beta 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 beta 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.