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<p>Alzheimer’s disease (AD), which affects millions globally, is marked by progressive cognitive decline and neurodegeneration driven by protein aggregation and chronic inflammation. Emerging evidence has implicated peptidyl arginine deiminase 4 (PAD4) activity and impaired autophagy as key contributors to disease progression. In this study, we explored the neuroprotective potential of DHA in an in vitro model of AD. DHA was administered before arachidonic acid (AA), a proinflammatory agent that mimics AD-like cellular stress. DHA treatment reduced PAD4 expression, enhanced autophagy-related gene expression, and attenuated inflammatory and oxidative stress markers. It also lowered amyloid-beta accumulation and preserved neuronal integrity. These outcomes suggest a potential dual mechanism by which DHA may influence Alzheimer’s-related pathology via PAD4 inhibition and autophagy stimulation in vitro. While these findings offer important mechanistic insights, further validation in animal models and clinical contexts is essential before therapeutic relevance can be confirmed.</p>

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Dual Mechanism of Docosahexaenoic acid (DHA) in Alzheimer’s Disease: PAD4 Inhibition and Autophagy Stimulation

  • 期刊论文

  • 发表日期：

    2025年5月3日

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  • Haleh Barmaki,
  • Alireza Nourazarian,
  • Hadi Yousefi,
  • Asghar Khalilnezhad,
  • Elham Shahriyari,
  • Fatemeh khaki-khatibi

摘要

Alzheimer’s disease (AD), which affects millions globally, is marked by progressive cognitive decline and neurodegeneration driven by protein aggregation and chronic inflammation. Emerging evidence has implicated peptidyl arginine deiminase 4 (PAD4) activity and impaired autophagy as key contributors to disease progression. In this study, we explored the neuroprotective potential of DHA in an in vitro model of AD. DHA was administered before arachidonic acid (AA), a proinflammatory agent that mimics AD-like cellular stress. DHA treatment reduced PAD4 expression, enhanced autophagy-related gene expression, and attenuated inflammatory and oxidative stress markers. It also lowered amyloid-beta accumulation and preserved neuronal integrity. These outcomes suggest a potential dual mechanism by which DHA may influence Alzheimer’s-related pathology via PAD4 inhibition and autophagy stimulation in vitro. While these findings offer important mechanistic insights, further validation in animal models and clinical contexts is essential before therapeutic relevance can be confirmed.