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Downregulation of NF-κB and NLRP3 in aging wildtype and amyloid β transgenic mice

ABSTRACT: Neuroinflammation is a key component of Alzheimer's disease (AD), and it may be driven by the activation of NFκB and NLRP3 signaling pathways. AD pathology, like amyloid-β, may exacerbate the activation of these pathways. We used a nucleic acid therapeutic (nanoligomer) cocktail targeting NFκB and NLRP3 to reduce inflamamtory signaling in aged wildtype mice and a transgenic mouse model of amyloid-β pathology (APP/PS1). Short-term (3 days) treatment reversed age- and amyloid-β-related gene sigantures, supporting the idea that this nanoligomer cocktail may have the potential to improve AD-related neuroinflammation and cognitive dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE303458 | GEO | 2025/07/25

REPOSITORIES: GEO

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Project description:Objective: 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.

Project description:Objective: Emerging evidence suggested that brain angiotensin-(1-7) (Ang-(1-7)) deficiency contributed 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 then isolated for high-throughput lncRNA sequencing to identify the most differentially expressed lncRNA following AVE0991 treatment. Afterward, the downstream pathway of this lncRNA in the anti-inflammatory action of AVE0991 were investigated using primary astrocytes. Results: The protection of AVE0991 against cognitive impairment and neuronal and synaptic damage in APP/PS1 mice was confirmed. For the first time, we demonstrated 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: These results suggest that AVE0991 inhibits astrocyte-mediated neuroinflammation via SNHG14/miR-223-3p/NLRP3 pathway. Moreover, these results reveal the underlying mechanisms by which Ang-(1-7) inhibits neuroinflammation under AD condition and uncovers the potential of its nonpeptide analogue AVE0991 in AD treatment.

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Downregulation of NF-κB and NLRP3 in aging wildtype and amyloid β transgenic mice

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