Wu Celeste Yin-Chieh, Zhang Yulan, Howard Peyton, Huang Fang, Lee Reggie Hui-Chao
Department of Neurology, Louisiana State University Health, LSU Health Sciences Center Shreveport, 1501 Kings Hwy, Shreveport, LA, 71103-3932, USA.
Institute for Cerebrovascular and Neuroregeneration Research, Louisiana State University Health, Shreveport, LA, USA.
Geroscience. 2025 Apr;47(2):2383-2397. doi: 10.1007/s11357-024-01424-5. Epub 2024 Nov 13.
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）是痴呆的主要病因，全球有超过5500万人受其影响，且常伴有抑郁和焦虑。这两者均对患者的生活质量产生重大影响，并给医疗系统带来巨大的社会和经济负担。确定导致AD患者心理和情绪缺陷的复杂调控机制将为治疗提供有前景的靶点。通过长链酰基辅酶A合成酶（ACSL）进行的ω-3（ω3）和ω-6脂肪酸（ω6-FA）生物合成对细胞功能和存活至关重要。这是因为ω3/6-FA在调节质膜、能量产生和炎症方面具有重要作用。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（如抑郁和焦虑）中的作用仍 largely未被探索。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。通过基于毛细管的免疫测定法发现，老年3xTg-AD小鼠海马中的ACSL3水平显著降低。ACAL3的这种降低与抑郁和焦虑样行为增加密切相关（通过强迫游泳、悬尾、高架十字迷宫和蔗糖偏好试验）。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（通过脑组学、基于毛细管的免疫测定法），从而缓解了抑郁和焦虑症状。本研究突出了ACSL3在大脑中的一种新的神经保护作用。靶向ACSL3将为治疗AD相关抑郁和焦虑提供一种创新方法。
