Tanshinone IIA improves Alzheimer's disease via RNA nuclear-enriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition characterized by oxidative stress and neuroinflammation. Tanshinone IIA (Tan-IIA), a bioactive compound isolated from Salvia miltiorrhiza plants, has shown potential neuroprotective effects; however, the mechanisms underlying such a function remain unclear.

AIM: To investigate potential Tan-IIA neuroprotective effects in AD and to elucidate their underlying mechanisms.

METHODS: Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology. To assess changes in oxidative stress and neuroinflammation, we performed enzyme-linked immunosorbent assay and western blotting. Additionally, the effect of Tan-IIA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Genetic changes related to the long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1)/microRNA (miRNA, miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction.

RESULTS: In vivo , Tan-IIA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice. In vitro experiments showed that Tan-IIA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability, apoptosis, oxidative stress, and neuroinflammation. In this process, the lncRNA NEAT1 - a potential therapeutic target - is highly expressed in AD mice and downregulated via Tan-IIA treatment. Mechanistically, NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p, which activates nuclear factor kappa-B (NF-κB) signaling, leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein, which exacerbates AD. Tan-IIA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling.

CONCLUSION: This study demonstrates that Tan-IIA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway, serving as a foundation for the development of innovative approaches for AD therapy.