Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans
Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans
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DOI：
10.1073/pnas.1107411108
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发表时间：
2011-09-06
影响因子：
11.1
通讯作者：
Sheline, Yvette I.
中科院分区：
文献类型：
--
作者：
Cirrito, John R.;Disabato, Brianne M.;Sheline, Yvette I.
β 淀粉样蛋白 (Aβ) 在大脑内以有毒低聚物和淀粉样斑块的形式聚集，似乎是引发阿尔茨海默病 (AD) 病变的致病事件。一种治疗策略是降低 Aβ 水平以限制其积累。某些神经递质受体的激活可以调节 Aβ 代谢。我们评估了 AD 小鼠模型和人类中血清素信号改变大脑 Aβ 水平和斑块的能力。在小鼠中，服用几种选择性血清素再摄取抑制剂 (SSRI) 抗抑郁药物后，脑间质液 (ISF) A β 水平降低了 25%。同样，直接将血清素输注到海马体中会降低 ISF A β 水平。如果用细胞外调节激酶（ERK）信号级联的抑制剂预处理小鼠，则 Aβ 的血清素依赖性减少会被逆转。长期使用 SSRI 类药物西酞普兰治疗，可使小鼠的脑斑块负荷减少 50%。为了测试血清素信号传导是否会影响人类的 Aβ 斑块，我们回顾性比较了过去 5 年内接触过抗抑郁药物的认知正常老年参与者与未接触过抗抑郁药物的参与者的大脑淀粉样蛋白负荷。通过使用匹兹堡化合物 B (PIB) 进行正电子发射断层扫描 (PET) 成像进行量化，接受抗抑郁药治疗的参与者的淀粉样蛋白负荷显着减少。扫描前 5 年内抗抑郁药物的累积使用时间与较少的斑块负荷相关。这些数据表明，在认知正常的个体中，血清素信号传导与 Aβ 积累较少有关。
Aggregation of amyloid-beta (A beta) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce A beta levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate A beta metabolism. We assessed the ability of serotonin signaling to alter brain A beta levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) A beta levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF A beta levels. Serotonin-dependent reductions in A beta were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact A beta plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less A beta accumulation in cognitively normal individuals.