Diminazene Ameliorates Neuroinflammation by Suppression of Astrocytic miRNA-224-5p/NLRP3 Axis in Alzheimer's Disease Model

XiaoJin Sun; Yang Deng; PengXin Ge; Qiang Peng; Ismatullah Soufiany; Lin Zhu; Rui Duan

doi:10.2147/JIR.S401385

Diminazene Ameliorates Neuroinflammation by Suppression of Astrocytic miRNA-224-5p/NLRP3 Axis in Alzheimer's Disease Model

J Inflamm Res. 2023 Apr 17:16:1639-1652. doi: 10.2147/JIR.S401385. eCollection 2023.

Authors

XiaoJin Sun^#¹, Yang Deng^#², PengXin Ge^#³, Qiang Peng⁴, Ismatullah Soufiany⁴, Lin Zhu⁴, Rui Duan⁴

Affiliations

¹ Faculty of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui, People's Republic of China.
² School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
³ Department of Pharmacy, Anhui Provincial Cancer Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People's Republic of China.
⁴ Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: ACE2/Ang(1-7)/Mas Receptor, the momentous component of the renin-angiotensin system, has been shown to be involved in Alzheimer's disease (AD). We had previously found that enhancing brain ACE2 activity ameliorated cognitive impairment and attenuated brain neuroinflammation in SAMP8 mice, an animal model of AD. However, the exact mechanism of action of Diminazene (DIZE) has not been revealed.

Methods: APP/PS1 mice were injected intraperitoneally with DIZE. Cognitive functions, neuronal and synaptic integrity, and inflammation-related markers were assessed by Morris water maze, Nissl staining, Western blotting and ELISA, respectively. Since astrocytes played a crucial role in AD-related neuroinflammation whilst miRNAs were reported to participate in modulating inflammatory responses, astrocytes of APP/PS1 mice were then isolated for high-throughput miRNAs sequencing to identify the most differentially expressed miRNA following DIZE treatment. Afterward, the downstream pathway of this miRNA in the anti-inflammatory action of DIZE was investigated using primary astrocytes.

Results: The results showed that DIZE alleviated cognitive impairment and neuronal and synaptic damage in APP/PS1 mice. Simultaneously, DIZE suppressed the secretion of pro-inflammatory cytokines and the expression of NLRP3 inflammasome. Importantly, miR-224-5p was significantly up-regulated in the astrocytes of APP/PS1 mice treated by DIZE, and NLRP3 is one of the targets of miR-224-5p. Upregulation of miR-224-5p inhibited the expression of NLRP3 in Aβ1-42-stimulated cells, whereas miR-224-5p downregulation reversed this effect. Furthermore, the inhibition of miR-224-5p could reverse the inhibitory effect of DIZE on astrocytic NLRP3 inflammasome.

Conclusion: These findings firstly suggested that DIZE could inhibit astrocyte-regulated neuroinflammation via miRNA-224-5p/NLRP3 pathway. Furthermore, our study reveals the underlying mechanism by which DIZE suppresses neuroinflammatory responses in AD mice and uncovers the potential of DIZE in AD treatment.

Keywords: Alzheimer’s disease; DIZE; NLRP3; astrocyte; miRNA-224-5p; neuroinflammation.

Grants and funding

This work was supported by the Natural Science Foundation of Jiangsu Province (BK20220196), Nanjing International Joint research and development Project (202201030), Project funded by China Postdoctoral Science Foundation (2022M711666), University Natural Science Project of Anhui Province (2022AH051534) and Xinghuo Talent Program of Nanjing First Hospital.