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<p>Despite understanding the pathophysiology of Alzheimer’s disease (AD), the mechanisms of neuronal regeneration mediated by oleanolic acid (OA) through m6A RNA methylation remain unexplored, forming the crux of this study. In a streptozotocin (STZ)-induced AD rat model, we administered OA and conducted behavioral tests to evaluate cognitive functions. We employed BrdU incorporation assays and immunofluorescence to investigate NSC proliferation, and Western blotting, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and MeRIP-qPCR assays to analyze protein expression and RNA stability. Bioinformatic predictions focused on the interaction between KLF5, YTHDF2, and FGF13. OA significantly reversed cognitive impairment and enhanced NSC differentiation in the AD model. The modulation of OA on KLF5 expression led to the repression of YTHDF2, which was pivotal in the m6A-dependent RNA decay of FGF13, promoting axonal regeneration. Furthermore, FGF13 harbors multiple m6A modification sites, which contribute to its mRNA stability and translation, thereby influencing neuronal polarization and migration. In addition, the neuroprotective mechanism of OA also involved the upregulation of NSCs, while impaired neurogenesis and reduced NSC function are known to be associated with AD pathology. This research reveals that OA’s therapeutic potential in AD is mediated through a previously unidentified mechanism involving modulation of m6A-dependent RNA regulation, highlighting the significance of m6A RNA methylation in neuronal regeneration. The findings pave the way for new therapeutic strategies targeting RNA modifications in neurodegenerative diseases.</p>

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Oleanolic acid modulates neuronal regeneration through KLF5-mediated FGF13 mRNA degradation to alleviate Alzheimer’s disease-like cognitive dysfunction

  • 期刊论文

  • 发表日期：

    2026年6月15日

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  • Dan Ren,
  • Jiangxi Xu,
  • Lan Xiao,
  • Ting Zhang,
  • Biyan Li,
  • Ruomeng Li,
  • Hong Zhu

摘要

Despite understanding the pathophysiology of Alzheimer’s disease (AD), the mechanisms of neuronal regeneration mediated by oleanolic acid (OA) through m6A RNA methylation remain unexplored, forming the crux of this study. In a streptozotocin (STZ)-induced AD rat model, we administered OA and conducted behavioral tests to evaluate cognitive functions. We employed BrdU incorporation assays and immunofluorescence to investigate NSC proliferation, and Western blotting, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and MeRIP-qPCR assays to analyze protein expression and RNA stability. Bioinformatic predictions focused on the interaction between KLF5, YTHDF2, and FGF13. OA significantly reversed cognitive impairment and enhanced NSC differentiation in the AD model. The modulation of OA on KLF5 expression led to the repression of YTHDF2, which was pivotal in the m6A-dependent RNA decay of FGF13, promoting axonal regeneration. Furthermore, FGF13 harbors multiple m6A modification sites, which contribute to its mRNA stability and translation, thereby influencing neuronal polarization and migration. In addition, the neuroprotective mechanism of OA also involved the upregulation of NSCs, while impaired neurogenesis and reduced NSC function are known to be associated with AD pathology. This research reveals that OA’s therapeutic potential in AD is mediated through a previously unidentified mechanism involving modulation of m6A-dependent RNA regulation, highlighting the significance of m6A RNA methylation in neuronal regeneration. The findings pave the way for new therapeutic strategies targeting RNA modifications in neurodegenerative diseases.