Choudhary Priyanka, Kumari Shilpa, Bagri Kajal, Deshmukh Rahul
Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, 151001, India.
Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab, 151401, India.
Inflammopharmacology. 2025 Apr;33(4):1775-1783. doi: 10.1007/s10787-025-01719-9. Epub 2025 Mar 27.
Ceramide is a key component of sphingolipid metabolism and functions as a lipid second messenger. Sphingolipids are crucial for maintaining the nervous system, particularly in differentiation and development. Ceramide supports hippocampal growth but, at elevated levels, can impair dendritic cell function. During aging and neurodegenerative diseases like Alzheimer's disease (AD), intracellular ceramide production and accumulation increase, negatively impacting cognitive functions. High ceramide levels are linked to the progression of AD pathology, significantly contributing to amyloid β (Aβ) accumulation, tau tangle formation, insulin resistance, oxidative stress, and neuroinflammation. Ceramide facilitates the production and aggregation of Aβ peptides, leading to neurotoxic plaque formation. Its dysregulation is associated with abnormal tau protein phosphorylation, resulting in neurofibrillary tangles (NFTs). In addition, elevated ceramide levels can trigger brain inflammation by promoting the release of pro-inflammatory cytokines and activating microglia. This accumulation also enhances oxidative stress in neurons, damaging cellular components such as proteins, lipids, and DNA. This review will help in deeper understanding of the molecular pathways altered via ceramide metabolism and accumulation involved in the AD pathology. The cellular and pathological mechanisms of ceramide and their impact on Alzheimer's disease pathophysiology. A deeper understanding of ceramide-mediated effects in aging and AD could pave the way for innovative therapeutic strategies targeting ceramide metabolism to treat neurodegenerative diseases and age-related cognitive decline.
神经酰胺是鞘脂代谢的关键成分，作为脂质第二信使发挥作用。鞘脂对于维持神经系统至关重要，尤其是在分化和发育过程中。神经酰胺支持海马体生长，但在水平升高时，会损害树突状细胞功能。在衰老以及诸如阿尔茨海默病（AD）等神经退行性疾病期间，细胞内神经酰胺的产生和积累会增加，对认知功能产生负面影响。高神经酰胺水平与AD病理进程相关，对淀粉样β（Aβ）积累、tau蛋白缠结形成、胰岛素抵抗、氧化应激和神经炎症有显著影响。神经酰胺促进Aβ肽的产生和聚集，导致神经毒性斑块形成。其失调与tau蛋白异常磷酸化有关，导致神经原纤维缠结（NFTs）。此外，升高的神经酰胺水平可通过促进促炎细胞因子的释放和激活小胶质细胞引发脑部炎症。这种积累还会增强神经元中的氧化应激，损害蛋白质、脂质和DNA等细胞成分。本综述将有助于更深入地了解通过神经酰胺代谢和积累而改变的分子途径，这些途径与AD病理相关。神经酰胺的细胞和病理机制及其对阿尔茨海默病病理生理学的影响。更深入地了解神经酰胺在衰老和AD中介导的作用，可为针对神经酰胺代谢的创新治疗策略铺平道路，以治疗神经退行性疾病和与年龄相关的认知衰退。
