Barmaki Haleh, Nourazarian Alireza, Yousefi Hadi, Khalilnezhad Asghar, Shahriyari Elham, Khaki-Khatibi Fatemeh
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
Mol Neurobiol. 2025 May 3. doi: 10.1007/s12035-025-05008-y.
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.
阿尔茨海默病（AD）在全球影响着数百万人，其特征是由蛋白质聚集和慢性炎症驱动的进行性认知衰退和神经退行性变。新出现的证据表明，肽基精氨酸脱亚氨酶4（PAD4）活性和自噬受损是疾病进展的关键因素。在本研究中，我们在AD的体外模型中探究了二十二碳六烯酸（DHA）的神经保护潜力。在花生四烯酸（AA）之前给予DHA，AA是一种模拟AD样细胞应激的促炎剂。DHA处理降低了PAD4表达，增强了自噬相关基因表达，并减弱了炎症和氧化应激标志物。它还降低了β-淀粉样蛋白的积累并保持了神经元完整性。这些结果表明了一种潜在的双重机制，通过该机制DHA可能在体外通过抑制PAD4和刺激自噬来影响阿尔茨海默病相关病理。虽然这些发现提供了重要的机制见解，但在确认治疗相关性之前，在动物模型和临床环境中进行进一步验证至关重要。
