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.

Abstract

OBJECTIVE:

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.

• Authors: Rui Duan, Si-Yu Wang, Bin Wei, Yang Deng, Xin-Xin Fu, Peng-Yu Gong, Yan E, Xiao-Jin Sun, Hai-Ming Cao, Jian-Quan Shi, Teng Jiang, Ying-Dong Zhang
• Journal: Journal of inflammation research (J Inflamm Res) Vol. 14 Pg. 7007-7019 ( 2021) ISSN: 1178-7031 [Print] New Zealand
• PMID: 34955647 (Publication Type: Journal Article)
• Copyright: © 2021 Duan et al.