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<p>The <i>APOE</i> genotype influences metabolic and neurodegenerative outcomes, with <i>APOE4</i> carriers at higher risk for Alzheimer’s disease (AD) and metabolic dysfunction. This study examines how long-term dietary interventions affect systemic metabolism, retinal structure/ function in <i>APOE3</i>-knock-in (KI, neutral for AD) and <i>APOE4</i>-KI mice. Humanized <i>APOE3</i> and <i>APOE4</i>-KI mice received either a control diet (CD) or a Western diet (WD) for 2, 6, or 12 months. Body weight, glucose metabolism, lipid profiles, retinal structure, function, vasculature, visual performance, and inflammatory markers were analyzed. WD induced early glucose intolerance in <i>APOE4</i> mice (2 months); <i>APOE3</i> mice showed impairment only after prolonged exposure (6–12 months). Notably, WD-fed <i>APOE3</i> mice exhibited more pronounced hyperlipidemia than <i>APOE4</i> mice. <i>APOE4</i> CD mice displayed early retinal thinning (6 months), while <i>APOE4</i> WD mice initially exhibited retinal swelling, followed by degeneration (12 months). WD exacerbated retinal vascular dysfunction in <i>APOE4</i> mice, with increased tortuosity and reduced vascular area. Elevated <i>Il1b</i> expression in WD-fed <i>APOE4</i> mice confirmed inflammation-associated retinal dysfunction. <i>APOE4</i> mice showed heightened dietary vulnerability, with WD worsening metabolic, retinal, and vascular impairments. While CD showed better glucose tolerance, it did not prevent retinal dysfunction. These findings underscore the need for genotype-specific dietary strategies to mitigate <i>APOE4</i>-associated risks.</p>

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High-fat Western diet induces retinal and metabolic alterations in APOE3 and APOE4 knock-in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Surabhi D. Abhyankar,
  • Qianyi Luo,
  • Gabriella D. Hartman,
  • Neha Mahajan,
  • Timothy W. Corson,
  • Adrian L. Oblak,
  • Bruce T. Lamb,
  • Ashay D. Bhatwadekar

摘要

The APOE genotype influences metabolic and neurodegenerative outcomes, with APOE4 carriers at higher risk for Alzheimer’s disease (AD) and metabolic dysfunction. This study examines how long-term dietary interventions affect systemic metabolism, retinal structure/ function in APOE3-knock-in (KI, neutral for AD) and APOE4-KI mice. Humanized APOE3 and APOE4-KI mice received either a control diet (CD) or a Western diet (WD) for 2, 6, or 12 months. Body weight, glucose metabolism, lipid profiles, retinal structure, function, vasculature, visual performance, and inflammatory markers were analyzed. WD induced early glucose intolerance in APOE4 mice (2 months); APOE3 mice showed impairment only after prolonged exposure (6–12 months). Notably, WD-fed APOE3 mice exhibited more pronounced hyperlipidemia than APOE4 mice. APOE4 CD mice displayed early retinal thinning (6 months), while APOE4 WD mice initially exhibited retinal swelling, followed by degeneration (12 months). WD exacerbated retinal vascular dysfunction in APOE4 mice, with increased tortuosity and reduced vascular area. Elevated Il1b expression in WD-fed APOE4 mice confirmed inflammation-associated retinal dysfunction. APOE4 mice showed heightened dietary vulnerability, with WD worsening metabolic, retinal, and vascular impairments. While CD showed better glucose tolerance, it did not prevent retinal dysfunction. These findings underscore the need for genotype-specific dietary strategies to mitigate APOE4-associated risks.