2. Academic Validation
  3. Apelin-13-Mediated Upregulation of METTL3 Ameliorates Alzheimer's Disease via Inhibiting Neuroinflammation Through m6A-Dependent Regulation of lncRNA BDNF-AS

Apelin-13-Mediated Upregulation of METTL3 Ameliorates Alzheimer's Disease via Inhibiting Neuroinflammation Through m6A-Dependent Regulation of lncRNA BDNF-AS

  • Biomolecules. 2025 Aug 18;15(8):1188. doi: 10.3390/biom15081188.
Li Han 1 2,  Siwen Wei 3,  Rong Wang 4,  Yiran Liu 4,  Yi Zhong 1,  Juan Fu 5,  Huaiqing Luo 4 6,  Meihua Bao 1 2
Affiliations

Affiliations

  • 1 Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, the First Clinical College, Changsha Medical University, Changsha 410219, China.
  • 2 Hunan Provincial Key Laboratory of the Traditional Chinese Medicine Agricultural Biogenomics, Changsha Medical University, Changsha 410219, China.
  • 3 Department of Immunology, School of Medicine, Jishou University, Jishou 416000, China.
  • 4 Department of Physiology, School of Basic Medical Sciences, Hunan Normal University, Changsha 410013, China.
  • 5 College of Biological and Pharmaceutical Engineering, Shandong University of Aeronautics, Binzhou 256603, China.
  • 6 Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, China.
PMID: 40867632 DOI: 10.3390/biom15081188
Abstract

Apelin-13, a neuropeptide, has been recognized for its neuroprotective properties. Our previous study found apelin-13 improves cognitive function in Alzheimer's disease (AD) rats by inhibiting neuroinflammation through upregulation of BDNF/TrkB signaling pathway. However, the precise mechanism by which apelin-13 modulates BDNF remains unclear. Thus, this study aimed to unravel the specific regulatory mechanism by which apelin-13 regulates BDNF. Bilaterally intracerebroventricular injection with Aβ25-35 was used to establish an in vivo model of AD. For the generation of METTL3 KO rats, the Crispr/Cas9 method was applied. PC12 cells were treated with Aβ25-35 to establish an in vitro model of AD. The cognitive function of the rats was evaluated with the Morris water maze and the novel object recognition test. Hippocampal damage and neuron loss were detected through H&E and immunofluorescent staining. METTL3, BDNF, TrkB, and p-TrkB were examined by Western blotting. Inflammation-related cytokines, IBA1, GFAP, IL-1β, and TNF-α were detected by Western blotting, immunofluorescent staining, ELISA, and qRT-PCR. m6A modification level was evaluated through MeRIP. A flow cytometer was applied to evaluate cell Apoptosis. Cell proliferation was examined using MTT. m6A methylation inhibitor DAA reverses the improvement effect of apelin-13 on cognitive function, hippocampal nerve damage, neuron loss, and neuroinflammation in Aβ25-35-treated rats. Further results showed that apelin-13 upregulated METTL3, BDNF-AS m6A methylation, inhibited BDNF-AS expression, and subsequently upregulated BDNF/TrkB signaling pathway and reduced neuroinflammation in in vivo and in vitro AD models in a dose-dependent manner. Knockdown of METTL3 abolished apelin-13's improvement effect in AD rats. Apelin-13-mediated upregulation of METTL3 enhances neuroinflammation inhibition and BDNF/TrkB signaling pathway via m6A-dependent downregulation of lncRNA BDNF-AS, thus ameliorating AD. Our study offers novel insights into the pathogenesis of AD and identifies potential drug targets for its treatment.

Keywords

Alzheimer’s disease; Apelin-13; METTL3; lncRNA BDNF-AS; m6A methylation; neuroinflammation.

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