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

摘要

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.