Journal of Inflammation Research (Dec 2021)

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

  • Duan R,
  • Wang SY,
  • Wei B,
  • Deng Y,
  • Fu XX,
  • Gong PY,
  • E Y,
  • Sun XJ,
  • Cao HM,
  • Shi JQ,
  • Jiang T,
  • Zhang YD

Journal volume & issue
Vol. Volume 14
pp. 7007 – 7019

Abstract

Read online

Rui Duan,1,* Si-Yu Wang,1,* Bin Wei,1 Yang Deng,2 Xin-Xin Fu,2 Peng-Yu Gong,1 Yan E,1 Xiao-Jin Sun,2 Hai-Ming Cao,1 Jian-Quan Shi,1 Teng Jiang,1 Ying-Dong Zhang1,2 1Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People’s Republic of China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, People’s Republic of China*These authors contributed equally to this workCorrespondence: Teng Jiang; Ying-Dong ZhangDepartment of Neurology, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Nanjing, Jiangsu, 210006, People’s Republic of ChinaEmail [email protected]; [email protected]: 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.Materials and Methods: 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.Results: 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.Conclusion: 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.Keywords: Alzheimer’s disease, AVE0991, lncRNAs, SNHG14, miR-223-3p, astrocyte, neuroinflammation

Keywords