Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model.
Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model.
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DOI：
10.1212/wnl.0000000000010733
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发表时间：
2020-11-10
期刊：
影响因子：
9.9
通讯作者：
Sheline YI
中科院分区：
文献类型：
--
作者：
Cirrito JR;Wallace CE;Yan P;Davis TA;Gardiner WD;Doherty BM;King D;Yuede CM;Lee JM;Sheline YI
几种神经递质受体激活改变淀粉样前体蛋白（APP）加工成β-淀粉样蛋白（Aβ）的信号通路。5-羟色胺通过一系列5-羟色胺受体信号传导抑制Aβ生成。我们认为，艾司西酞普兰是抑制5-羟色胺转运蛋白SERT的最特异性选择性5-羟色胺再摄取抑制剂（SSRI），可抑制小鼠的Aβ水平。我们假设，艾司西酞普兰急性治疗可减少Aβ生成，这将反映为Aβ斑块负荷的长期显著减少。我们进行了体内微透析和体内双光子成像，分别评估了用溶剂或艾司西酞普兰治疗的APP/早老素1阿尔茨海默病小鼠模型中脑间质液（ISF）Aβ和Aβ斑块大小随时间的变化。我们还用艾司西酞普兰长期治疗小鼠，以确定对斑块组织学的影响。艾司西酞普兰通过增加APP的α-分泌酶裂解，使ISF Aβ急剧降低25%。长期给予艾司西酞普兰2.5和5 mg/d分别使斑块负荷显著降低28%和34%。5 mg/kg的艾司西酞普兰不能清除现有的斑块，但随着时间的推移完全阻止了个体斑块的生长。艾司西酞普兰显著降低了小鼠中的Aβ，与先前在接受SSRI急性给药的人类中的发现相似。
Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into β-amyloid (Aβ). Serotonin signaling through a subset of serotonin receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter SERT, would suppress Aβ levels in mice. We hypothesized that acute treatment with escitalopram would reduce Aβ generation, which would be reflected chronically with a significant reduction in Aβ plaque load. We performed in vivo microdialysis and in vivo 2-photon imaging to assess changes in brain interstitial fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/presenilin 1 mouse model of Alzheimer disease treated with vehicle or escitalopram. We also chronically treated mice with escitalopram to determine the effect on plaques histologically. Escitalopram acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of escitalopram significantly reduced plaque load by 28% and 34% at 2.5 and 5 mg/d, respectively. Escitalopram at 5 mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time. Escitalopram significantly reduced Aβ in mice, similar to previous findings in humans treated with acute dosing of an SSRI.