ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/011/SRR18391111/SRR18391111.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/008/SRR18391108/SRR18391108.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/010/SRR18391110/SRR18391110.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/013/SRR18391113/SRR18391113.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/012/SRR18391112/SRR18391112.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR183/009/SRR18391109/SRR18391109.fastq.gzprimaryOK200GenomicsNanjing first hospitalhttps://www.ebi.ac.uk/ena/browser/view/PRJNA818040Mus musculusxref:PubMed:37092127Objective: The protective components ACE2/Ang(1-7)/MasR of the renin-angiotensin system has been verified to play a role in Alzheimer's disease (AD). Our previous study revealed that enhancement of brain ACE2 activity, an important effector of RAS, by diminazene aceturate (DIZE) ameliorated Alzheimer's disease-like neuropathology and attenuated neuroinflammation in the brain of SAMP8 mice. However, the potential molecular mechanisms by which DIZE modulates neuroinflammation in AD remain unclear. Materials and Methods: APP/PS1 mice were injected intraperitoneally with DIZE (once a day for 30 consecutive days). Cognitive functions, neuronal and synaptic integrity, and inflammation-related markers were assessed by Morris water maze, Nissl staining, Western blot 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 results firstly suggested that DIZE inhibits astrocyte-mediated neuroinflammation via miR-224-5p/NLRP3 pathway. Moreover, these results reveal the underlying mechanisms by which DIZE inhibits neuroinflammation under AD condition and uncovers the potential of DIZE in AD treatment. Overall design: Astrocytes miRNA profiles of 8 months old APP/PS1 mice and APP/PS1 mice were treated with DIZEENAfalseACE2 activator diminazene modulates astrocyte-mediated neuroinflammation via miR-224-5p/NLRP3 pathway and offers neuroprotection in a transgenic mouse model of Alzheimer’s diseaseACE2 activator diminazene modulates astrocyte-mediated neuroinflammation via miR-224-5p/NLRP3 pathway and offers neuroprotection in a transgenic mouse model of Alzheimer’s disease2025-09-172023-05-02PRJNA818040GSE1990281009037092127