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<p>Alzheimer’s disease (AD) is associated with mitochondrial dysfunction and impaired energy metabolism in astrocytes. Although ghrelin is known to exert neuroprotective effects, the mechanisms through which it modulates astrocyte bioenergetics under AD-like conditions remain incompletely defined. In primary astrocytes treated with Aβ<sub>25-35</sub> oligomers, ghrelin attenuated mitochondrial damage, reducing ROS and enhancing mitochondrial membrane potential (ΔΨm) and respiratory complex activities. Glycolytic function was partially restored, as evidenced by upregulation of key enzymes, increased glucose uptake, lactate release, and NAD<sup>+</sup>/NADH ratio. Ghrelin inhibited autophagosome formation while enhancing mitophagy (increased LC3II/I and Parkin) and suppressed inflammation. In co-culture models, these metabolic improvements enhanced astrocytic support for neurons, reducing apoptosis and promoting neurite growth, an effect abolished by the glycolytic inhibitor 2-DG. Mechanistically, ghrelin upregulated uncoupling protein 2 (UCP2), which inhibited forkhead box protein O1 (FOXO1) nuclear translocation. In Aβ<sub>25-35</sub>-injected mice with UCP2 or FOXO1 modulation, ghrelin improved cognitive performance and reduced pathology, effects that were negated by UCP2 knockdown and partially rescued by FOXO1 knockdown. In conclusion, ghrelin ameliorates Aβ-induced astrocyte dysfunction involving the UCP2-FOXO1 pathway, partially restoring mitochondrial integrity, glycolytic metabolism, and neurotrophic support, suggesting its therapeutic potential.</p>

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Ghrelin Ameliorates Alzheimer’s Disease-Associated Astrocyte Dysfunction via UCP2-Mediated Inhibition of FOXO1 Nuclear Translocation

  • 期刊论文

  • 发表日期：

    2026年1月1日

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  • Yaoxue Guo,
  • Xueyan Wang,
  • Lixiang Zhang,
  • Xing Liu,
  • Pu Lu,
  • Furu Liang,
  • Jing Wu,
  • Junli Zhao,
  • Yan Hai

摘要

Alzheimer’s disease (AD) is associated with mitochondrial dysfunction and impaired energy metabolism in astrocytes. Although ghrelin is known to exert neuroprotective effects, the mechanisms through which it modulates astrocyte bioenergetics under AD-like conditions remain incompletely defined. In primary astrocytes treated with Aβ25-35 oligomers, ghrelin attenuated mitochondrial damage, reducing ROS and enhancing mitochondrial membrane potential (ΔΨm) and respiratory complex activities. Glycolytic function was partially restored, as evidenced by upregulation of key enzymes, increased glucose uptake, lactate release, and NAD+/NADH ratio. Ghrelin inhibited autophagosome formation while enhancing mitophagy (increased LC3II/I and Parkin) and suppressed inflammation. In co-culture models, these metabolic improvements enhanced astrocytic support for neurons, reducing apoptosis and promoting neurite growth, an effect abolished by the glycolytic inhibitor 2-DG. Mechanistically, ghrelin upregulated uncoupling protein 2 (UCP2), which inhibited forkhead box protein O1 (FOXO1) nuclear translocation. In Aβ25-35-injected mice with UCP2 or FOXO1 modulation, ghrelin improved cognitive performance and reduced pathology, effects that were negated by UCP2 knockdown and partially rescued by FOXO1 knockdown. In conclusion, ghrelin ameliorates Aβ-induced astrocyte dysfunction involving the UCP2-FOXO1 pathway, partially restoring mitochondrial integrity, glycolytic metabolism, and neurotrophic support, suggesting its therapeutic potential.