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<p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder lacking effective disease-modifying therapies. A promising regenerative approach involves enhancing endogenous neurogenic capacity within the injured brain. Reactive astrocytes—stellate-like cells in the AD brain—may contribute to a pro-neurogenic environment through transcription factors (TFs) such as neurogenin 2 (NGN2) and SOX-11. This process is tightly regulated by epigenetic mechanisms, particularly SIRT-1, a neuroprotective histone deacetylase that modulates TF activity and neuronal fate. Vitamin A (V<sub>A</sub>), a key regulator of differentiation and epigenetic remodeling via its active metabolite retinoic acid, is stored in astrocytes and hepatic stellate cells (HSCs). We hypothesized that AD-related astrocyte activation depletes cerebral V<sub>A</sub>, mobilizes hepatic stores, contributes to liver fibrosis, and that V<sub>A</sub> supplementation may restore astrocytic function, activate endogenous TFs via SIRT-1, and drive cholinergic neuron regeneration. In a scopolamine (SCO)-induced AD rat model, V<sub>A</sub> biodistribution was traced using confocal microscopy. Brain and liver V<sub>A</sub> deficiency were confirmed via retinol-binding protein (RBP) and ALDH1A1 expressions. Rats received V<sub>A</sub> (1500, 3000, or 4500 IU/kg/day) or donepezil. Outcomes included neurogenesis (DCX), NGN2/SOX-11 expression, SIRT-1 activation, cholinergic regeneration, amyloid-β deposition, and serum tau. Liver fibrosis was assessed via TGF-β, hydroxyproline and histopathologically. AD induced systemic V<sub>A</sub> depletion and liver fibrosis. Medium-dose V<sub>A</sub> (VAMD) significantly enhanced neurogenesis, TF expression, SIRT-1 activation, cholinergic regeneration, and reversed liver fibrosis. VAMD demonstrated neuroregenerative and antifibrotic effects, indicating a possible therapeutic role in AD.</p>

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Vitamin a modulates neurogenesis-associated pathways and cholinergic signaling in Alzheimer’s disease: potential role of reactive astrocytes via NGN2/SOX-11 and SIRT-1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月25日

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  • Nesrine Saeid El-Mezayen,
  • Yara Alaa Eesa,
  • Wed Alaa Hassan,
  • Dina Ahmed Aly,
  • Yassmen Soliman Saafan,
  • Eman Mahmod Khedr,
  • Aliaa Sherief,
  • Eman Ali Elkordy

摘要

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder lacking effective disease-modifying therapies. A promising regenerative approach involves enhancing endogenous neurogenic capacity within the injured brain. Reactive astrocytes—stellate-like cells in the AD brain—may contribute to a pro-neurogenic environment through transcription factors (TFs) such as neurogenin 2 (NGN2) and SOX-11. This process is tightly regulated by epigenetic mechanisms, particularly SIRT-1, a neuroprotective histone deacetylase that modulates TF activity and neuronal fate. Vitamin A (VA), a key regulator of differentiation and epigenetic remodeling via its active metabolite retinoic acid, is stored in astrocytes and hepatic stellate cells (HSCs). We hypothesized that AD-related astrocyte activation depletes cerebral VA, mobilizes hepatic stores, contributes to liver fibrosis, and that VA supplementation may restore astrocytic function, activate endogenous TFs via SIRT-1, and drive cholinergic neuron regeneration. In a scopolamine (SCO)-induced AD rat model, VA biodistribution was traced using confocal microscopy. Brain and liver VA deficiency were confirmed via retinol-binding protein (RBP) and ALDH1A1 expressions. Rats received VA (1500, 3000, or 4500 IU/kg/day) or donepezil. Outcomes included neurogenesis (DCX), NGN2/SOX-11 expression, SIRT-1 activation, cholinergic regeneration, amyloid-β deposition, and serum tau. Liver fibrosis was assessed via TGF-β, hydroxyproline and histopathologically. AD induced systemic VA depletion and liver fibrosis. Medium-dose VA (VAMD) significantly enhanced neurogenesis, TF expression, SIRT-1 activation, cholinergic regeneration, and reversed liver fibrosis. VAMD demonstrated neuroregenerative and antifibrotic effects, indicating a possible therapeutic role in AD.