Alzheimer’s disease (AD), the leading cause of dementia, affects over 55 million people worldwide and is often accompanied by depression and anxiety. Both significantly impact patients’ quality of life and impose substantial societal and economic burdens on healthcare systems. Identifying the complex regulatory mechanisms that contribute to the psychological and emotional deficits in AD will provide promising therapeutic targets. Biosynthesis of omega-3 (ω3) and omega-6 fatty acids (ω6-FA) through long-chain acyl-CoA synthetases (ACSL) is crucial for cell function and survival. This is due to ω3/6-FA’s imperative role in modulating the plasma membrane, energy production, and inflammation. While ACSL dysfunction is known to cause heart, liver, and kidney diseases, the role of ACSL in pathological conditions in the central nervous system (e.g., depression and anxiety) remains largely unexplored. The impact of ACSLs on AD-related depression and anxiety was investigated in a mouse model of Alzheimer’s disease (3xTg-AD). ACSL3 levels were significantly reduced in the hippocampus of aged 3xTg-AD mice (via capillary-based immunoassay). This reduction in ACAL3 was closely associated with increased depression and anxiety-like behavior (via forced swim, tail suspension, elevated plus maze, and sucrose preference test). Upregulation of ACSL3 via adenovirus in aged 3xTg-AD mice led to increased protein levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor C (VEGF-C) (via brain histology, capillary-based immunoassay), resulting in alleviation of depression and anxiety symptoms. The present study highlights a novel neuroprotective role of ACSL3 in the brain. Targeting ACSL3 will offer an innovative approach for treating AD-related depression and anxiety.

阿尔茨海默病 （AD） 是痴呆的主要原因，影响着全球超过 5500 万人，并且通常伴有抑郁和焦虑。两者都会严重影响患者的生活质量，并给医疗保健系统带来巨大的社会和经济负担。确定导致 AD 心理和情绪缺陷的复杂调节机制将提供有希望的治疗靶点。通过长链酰基辅酶 A 合成酶 （ACSL） 合成 omega-3 （ω3） 和 omega-6 脂肪酸 （ω6-FA） 的生物合成对细胞功能和生存至关重要。这是由于 ω3/6-FA 在调节质膜、能量产生和炎症方面的重要作用。虽然已知 ACSL 功能障碍会导致心脏、肝脏和肾脏疾病，但 ACSL 在中枢神经系统病理状况（例如抑郁和焦虑）中的作用在很大程度上仍未得到探索。在阿尔茨海默病小鼠模型 （3xTg-AD） 中研究了 ACSL 对 AD 相关抑郁和焦虑的影响。老年 3xTg-AD 小鼠海马中 ACSL3 水平显著降低 （通过基于毛细血管的免疫测定）。ACAL3 的这种降低与抑郁和焦虑样行为的增加密切相关 （通过强迫游泳、悬尾、高架加迷宫和蔗糖偏好测试）。在老年 3xTg-AD 小鼠中，通过腺病毒上调 ACSL3 导致脑源性神经营养因子 （BDNF） 和血管内皮生长因子 C （VEGF-C） 的蛋白水平升高 （通过脑组织学，基于毛细血管的免疫测定），从而缓解抑郁和焦虑症状。本研究强调了 ACSL3 在大脑中的一种新的神经保护作用。 靶向 ACSL3 将为治疗 AD 相关的抑郁和焦虑提供一种创新方法。