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<p>Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, neuroinflammation, and systemic comorbidities, yet disease-modifying therapies remain elusive. Here, we show that partial epigenetic reprogramming via brain-restricted expression of Oct4, Sox2, and Klf4 (OSK) restores neuronal and neuroimmune homeostasis without loss of cellular identity. In APP/PS1 mice, OSK reprogramming improves cognitive performance across disease stages, reduces amyloid-β deposition, attenuates microglial activation, preserves synaptic integrity, and limits neuronal apoptosis. Mechanistically, reduced representation bisulfite sequencing reveals widespread reversal of AD-associated DNA methylation patterns, which is dependent on Tet2-mediated demethylation, establishing epigenetic rejuvenation as a key driver of functional recovery. Unexpectedly, brain-restricted OSK reprogramming also ameliorates systemic bone loss by reshaping brain-derived extracellular vesicle signaling, including modulation of miR-483-5p, thereby restoring osteogenic capacity. Together, these findings identify partial epigenetic reprogramming as a strategy to rewire neuro-immune circuits and link central nervous system rejuvenation to peripheral tissue homeostasis, providing a conceptual framework for targeting both neurodegeneration and its systemic consequences in AD.</p> Graphical abstract <p></p>

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Epigenetic brain reprogramming rejuvenates neuro-immune circuits to reverse Alzheimer’s disease pathology and systemic bone loss

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月28日

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  • Mei-Dan Wan,
  • Xi-Xi Liu,
  • Teng-Fei Wan,
  • Yi-Wei Liu,
  • Ya-Ling Jiang,
  • Jing-Tao Zou,
  • Bin Jiao,
  • Qian-Qian Liu,
  • Ling Jin,
  • Ran Duan,
  • Zun Wang,
  • Chun-Gu Hong,
  • Xin Wang,
  • Xin-Yue Hu,
  • Xin-Xin Liao,
  • Jia Cao,
  • Lu Shen,
  • Hui Xie,
  • Zhen-Xing Wang

摘要

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, neuroinflammation, and systemic comorbidities, yet disease-modifying therapies remain elusive. Here, we show that partial epigenetic reprogramming via brain-restricted expression of Oct4, Sox2, and Klf4 (OSK) restores neuronal and neuroimmune homeostasis without loss of cellular identity. In APP/PS1 mice, OSK reprogramming improves cognitive performance across disease stages, reduces amyloid-β deposition, attenuates microglial activation, preserves synaptic integrity, and limits neuronal apoptosis. Mechanistically, reduced representation bisulfite sequencing reveals widespread reversal of AD-associated DNA methylation patterns, which is dependent on Tet2-mediated demethylation, establishing epigenetic rejuvenation as a key driver of functional recovery. Unexpectedly, brain-restricted OSK reprogramming also ameliorates systemic bone loss by reshaping brain-derived extracellular vesicle signaling, including modulation of miR-483-5p, thereby restoring osteogenic capacity. Together, these findings identify partial epigenetic reprogramming as a strategy to rewire neuro-immune circuits and link central nervous system rejuvenation to peripheral tissue homeostasis, providing a conceptual framework for targeting both neurodegeneration and its systemic consequences in AD.

Graphical abstract