Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo.
Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo.
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DOI：
10.1186/s13024-016-0112-5
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发表时间：
2016-06-18
影响因子：
15.1
通讯作者：
Cirrito JR
中科院分区：
文献类型：
--
作者：
Fisher JR;Wallace CE;Tripoli DL;Sheline YI;Cirrito JR
淀粉样蛋白-β (a β)聚集成不溶性斑块是阿尔茨海默病（AD）的标志性病理。先前的研究表明，选择性5 -羟色胺再摄取抑制剂（SSRI）化合物增加5 -羟色胺水平可降低阿尔茨海默病小鼠模型脑间质液（ISF）和人类脑脊液中的a β。我们研究了哪种5-羟色胺受体（5-HTR）亚型和下游效应物是导致这种减少的原因。5-HT4R、5-HT6R和5-HT7R激动剂可显著降低ISF β，而其他受体亚型激动剂则无此作用。此外，蛋白激酶A （PKA）的抑制阻断了西酞普兰（一种SSRI）对ISF Aβ水平的影响。血清素信号传导似乎不会改变基因表达以降低急性时间内的Aβ水平，但可能在细胞质内起作用以增加α-分泌酶的酶活性。α-分泌酶的广泛药理抑制增加了ISF Aβ并阻断了西酞普兰的作用。总的来说，这些研究绘制了连接5 -羟色胺受体与脑ISF β抑制的主要信号成分。这些结果表明，ISF β的减少是由一组选定的5-HTRs介导的，为AD的靶向治疗开辟了未来的途径。本文的在线版本（doi:10.1186/s13024-016-0112-5）包含补充材料，授权用户可使用。
The aggregation of amyloid-β (Aβ) into insoluble plaques is a hallmark pathology of Alzheimer’s disease (AD). Previous work has shown increasing serotonin levels with selective serotonin re-uptake inhibitor (SSRI) compounds reduces Aβ in the brain interstitial fluid (ISF) in a mouse model of AD and in the cerebrospinal fluid of humans. We investigated which serotonin receptor (5-HTR) subtypes and downstream effectors were responsible for this reduction. Agonists of 5-HT4R, 5-HT6R, and 5-HT7R significantly reduced ISF Aβ, but agonists of other receptor subtypes did not. Additionally, inhibition of Protein Kinase A (PKA) blocked the effects of citalopram, an SSRI, on ISF Aβ levels. Serotonin signaling does not appear to change gene expression to reduce Aβ levels in acute timeframes, but likely acts within the cytoplasm to increase α-secretase enzymatic activity. Broad pharmacological inhibition of putative α-secretases increased ISF Aβ and blocked the effects of citalopram. In total, these studies map the major signaling components linking serotonin receptors to suppression of brain ISF Aβ. These results suggest the reduction in ISF Aβ is mediated by a select group of 5-HTRs and open future avenues for targeted therapy of AD. The online version of this article (doi:10.1186/s13024-016-0112-5) contains supplementary material, which is available to authorized users.