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 Aβ 1-42 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.

Non-coding RNAs: The Neuroinflammatory Regulators in Neurodegenerative Diseases

“…In addition, lncRNA HOTTIP was found to enhance NLRP3 activation by targeting and inhibiting miR-615-3p in the PD model (67). lncRNA-SNHG14 was found to down-regulate miR-223-3p and then up-regulate NLRP3 expression in the AD study (68). While miR-212 attenuated neuroinflammation in AD rats by inhibiting SP1 expression to block BACE1-induced NLRP3 activation (69).…”

Long Non-coding RNAs, Extracellular Vesicles and Inflammation in Alzheimer’s Disease

“…In astrocytes from the transgenic APP/PSEN mice model, SNHG14 was reported to sponge miR-223-3p, which directly targets and restrains NLRP3 inflammasome. In this model, angiotensin analogs inhibit inflammation and prevent cognitive impairment by inhibiting SNHG14, thus restoring miR-223-3p function [99]. Exercise that improves cognition and reduces inflammation markers, can also reduce SNG14 levels, in mice models and AD patients [100].…”

“…Small Nucleolar RNA Host Gene 14 (SNHG14) is another member of the SNHG family and has an essential role in promoting pro-inflammatory microglia activation [99]. In astrocytes from the transgenic APP/PSEN mice model, SNHG14 was reported to sponge miR-223-3p, which directly targets and restrains NLRP3 inflammasome.…”

Glial Cells and Brain Diseases: Inflammasomes as Relevant Pathological Entities

“…In this context, efforts have been made to ameliorate neuroinflammation in AD to find a therapeutic strategy that improves the outcome of the patients. For example, it has been proposed that glucagon-like peptide-1 analogs could mitigate astrocytic NLRP2 activation in 5xFAD transgenic mice, improving cognitive dysfunction in vivo and protecting astrocytes in vitro ( Zhang et al, 2022a ); in APP/PS1 mice, AVE0991 —an angiotensin-(1-7) analog— was effective in inhibiting astrocyte-mediated neuroinflammation via the SNHG14/miR-223-3p/NLRP3 pathway ( Duan et al, 2021 ). Treatment with Aβ to astrocytes promotes NLRP3 inflammasome activation.…”