Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin.
Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin.
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使用神经元来源的细胞外囊泡探索患有双相抑郁症的成人的大脑胰岛素抵抗。
DOI：
10.1016/j.jpsychires.2020.12.007
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发表时间：
2021-01
影响因子：
4.8
通讯作者：
McIntyre RS
中科院分区：
文献类型：
--
作者：
Mansur RB;Delgado-Peraza F;Subramaniapillai M;Lee Y;Iacobucci M;Nasri F;Rodrigues N;Rosenblat JD;Brietzke E;Cosgrove VE;Kramer NE;Suppes T;Raison CL;Fagiolini A;Rasgon N;Chawla S;Nogueras-Ortiz C;Kapogiannis D;McIntyre RS
越来越多的证据表明胰岛素信号传导受阻参与了双相情感障碍(BD)的发病。在这里，我们的目标是使用一种创新的技术直接探索神经元胰岛素信号的潜在作用，该技术基于富含神经元起源的血浆细胞外小泡(NEVS)的生物标记物。我们利用了一项随机、双盲、安慰剂对照、为期12周的临床试验的血浆样本，评估英夫利昔单抗作为双相抑郁的治疗方法。我们使用针对神经元标记L1CAM的免疫沉淀法从基线和第2、6和12周(终点)收集的样本中分离出NEV，并使用免疫分析方法测量NEV生物标记物。我们评估了神经元胰岛素信号在其第一个节点(IR-1)，并沿着规范的(Akt，GSK-3β，p70S6K)和替代(ERK1/2，JNK和p38-MAPK)通路。一组参与者(n=27)在基线和终点时也接受了全脑磁共振成像(MRI)。治疗前，胰岛素信号的Nev生物标志物与认知功能和MRI测量(即海马区和腹内侧额前皮质[vmPFC]体积)独立相关。事实上，IRS-1丝氨酸312位的磷酸化(pS312-IRS-1)是胰岛素抵抗的一个指标，它与认知功能障碍之间的关联是由vmPFC体积介导的。在纵向分析中，与安慰剂相比，接受英夫利昔单抗治疗的患者增加了替代途径中蛋白质的磷酸化。英夫利昔单抗是一种已知具有胰岛素敏化特性的肿瘤坏死因子-α拮抗剂。与英夫利昔单抗无应答者和安慰剂应答者相比，英夫利昔单抗应答者的磷酸化JNK水平显著增加。此外，英夫利昔单抗治疗导致脑体积的MRI测量增加；与治疗相关的前额叶皮质背外侧体积的变化是由胰岛素替代途径的生物标记物的变化所介导的。总而言之，我们的发现支持脑胰岛素信号是进一步机制和治疗研究的目标的想法。
Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3β, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.
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