Angiotensin-(1-7) Analogue AVE0991 Modulates Astrocyte-Mediated Neuroinflammation via lncRNA SNHG14/miR-223-3p/NLRP3 Pathway and Offers Neuroprotection in a Transgenic Mouse Model of Alzheimer's Disease.
Angiotensin-(1-7) Analogue AVE0991 Modulates Astrocyte-Mediated Neuroinflammation via lncRNA SNHG14/miR-223-3p/NLRP3 Pathway and Offers Neuroprotection in a Transgenic Mouse Model of Alzheimer's Disease.
复制标题
血管紧张素-(1-7) 类似物 AVE0991 通过 lncRNA SNHG14/miR-223-3p/NLRP3 途径调节星形胶质细胞介导的神经炎症，并在阿尔茨海默病转基因小鼠模型中提供神经保护
DOI：
10.2147/jir.s343575
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发表时间：
2021
影响因子：
4.5
通讯作者：
Zhang YD
中科院分区：
文献类型：
--
作者：
Duan R;Wang SY;Wei B;Deng Y;Fu XX;Gong PY;E Y;Sun XJ;Cao HM;Shi JQ;Jiang T;Zhang YD
新出现的证据表明，脑血管紧张素-(1-7)（Ang-(1-7)）缺乏与阿尔茨海默病（AD）的发病机制有关。同时，我们之前的研究表明，恢复脑Ang-(1-7)水平通过抑制AD进展过程中的炎症反应提供神经保护。然而，Ang-(1-7)调节神经炎症的潜在分子机制尚不清楚。APP/PS1小鼠腹腔注射AVE0991 （Ang-(1-7)的非肽类似物），每天1次，连续30天。评估认知功能、神经元和突触完整性以及炎症相关标志物。由于星形胶质细胞在ad相关的神经炎症中起着至关重要的作用，而长链非编码rna （lncRNAs）被报道参与调节炎症反应，因此我们分离APP/PS1小鼠的星形胶质细胞进行高通量lncRNA测序，以鉴定AVE0991治疗后表达差异最大的lncRNA。随后，我们利用原代星形胶质细胞研究了该lncRNA在AVE0991抗炎作用中的下游通路。AVE0991可改善APP/PS1小鼠的空间认知障碍，减轻神经元和突触损伤。AVE0991对APP/PS1小鼠脑内Aβ1-42水平无影响。通过高通量lncRNA测序，我们的体外研究首次证明了AVE0991通过lncRNA snhg14依赖的方式抑制星形细胞NLRP3炎症小体介导的神经炎症。SNHG14是miR-223-3p的海绵，而NLRP3是星形胶质细胞中miR-223-3p的直接靶点。此外，miR-223-3p参与了ave0991诱导的星形细胞NLRP3炎症小体的抑制。我们的研究结果表明，Ang-(1-7)类似物AVE0991通过SNHG14/miR-223-3p/NLRP3途径抑制星形胶质细胞介导的神经炎症，并在APP/PS1小鼠中提供神经保护。这些发现揭示了Ang-(1-7)在AD条件下抑制神经炎症的潜在机制，并揭示了其非肽类似物AVE0991在AD治疗中的潜力。
Emerging evidence suggests that brain angiotensin-(1–7) (Ang-(1–7)) deficiency contributes to the pathogenesis of Alzheimer’s disease (AD). Meanwhile, our previous studies revealed that restoration of brain Ang-(1–7) levels provided neuroprotection by inhibition of inflammatory responses during AD progress. However, the potential molecular mechanisms by which Ang-(1–7) modulates neuroinflammation remain unclear. APP/PS1 mice were injected intraperitoneally with AVE0991 (a nonpeptide analogue of Ang-(1–7)) once a day for 30 consecutive days. Cognitive functions, neuronal and synaptic integrity, and inflammation-related markers were assessed. Since astrocytes played a crucial role in AD-related neuroinflammation whilst long noncoding RNAs (lncRNAs) were reported to participate in modulating inflammatory responses, astrocytes of APP/PS1 mice were isolated for high-throughput lncRNA sequencing to identify the most differentially expressed lncRNA following AVE0991 treatment. Afterward, the downstream pathways of this lncRNA in the anti-inflammatory action of AVE0991 were investigated using primary astrocytes. AVE0991 rescued spatial cognitive impairments and alleviated neuronal and synaptic damage in APP/PS1 mice. The levels of Aβ1-42 in the brain of APP/PS1 mice were not affected by AVE0991. By employing high-throughput lncRNA sequencing, our in vitro study demonstrated for the first time that AVE0991 suppressed astrocytic NLRP3 inflammasome-mediated neuroinflammation via a lncRNA SNHG14-dependent manner. SNHG14 acted as a sponge of miR-223-3p while NLRP3 represented a direct target of miR-223-3p in astrocytes. In addition, miR-223-3p participated in the AVE0991-induced suppression of astrocytic NLRP3 inflammasome. Our results suggest that Ang-(1–7) analogue AVE0991 inhibits astrocyte-mediated neuroinflammation via SNHG14/miR-223-3p/NLRP3 pathway and offers neuroprotection in APP/PS1 mice. These findings reveal the underlying mechanisms by which Ang-(1–7) inhibits neuroinflammation under AD condition and uncover the potential of its nonpeptide analogue AVE0991 in AD treatment.