Saipuljumri Eka Norfaishanty, Zeng Jialiu, Lo Chih Hung
Program in Neuroscience & Cognitive Science, University of Arizona, Tucson, AZ, USA.
Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, NY, USA.
Neural Regen Res. 2025 Jul 5. doi: 10.4103/NRR.NRR-D-25-00432.
Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are increasingly associated with metabolic dysfunction, including obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease. Central to this connection is the dysregulation of lipid metabolism, which extends beyond peripheral tissues to the brain, defective autolysosomal function, oxidative stress, inflammation, and insulin resistance. Lipids, which constitute over half of dry weight of the brain, play critical roles in energy provision, structural integrity, and synaptic function. Dysregulation of lipid metabolism contributes to neuroinflammation, impaired neuronal function, and disrupted blood-brain barrier integrity. Palmitic acid, a saturated fatty acid abundant in high-fat diets, serves as a key model for studying lipid-induced toxicity (lipotoxicity) in the brain. Palmitic acid disrupts autophagy and lysosomal function, mitochondrial function, triggering oxidative stress, contributing to neuroinflammation and neurodegeneration. These effects are particularly pronounced in neurons, which are highly susceptible to lipid-induced toxicity due to their high metabolic demands. Glial cells, including astrocytes, microglia, and oligodendrocytes, also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation, further contributing to neuroinflammation and demyelination. Therapeutic strategies, such as supplementation with polyunsaturated fatty acids, AMP-activated protein kinase activation, and lysosome-targeted interventions, show promise in mitigating palmitic acid-induced lipotoxicity and restoring cellular homeostasis. This review comprehensively examines palmitic acid-induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types, including neurons, astrocytes, microglia, and oligodendrocytes. Additionally, it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions. Advances in multi-omics technologies and a deeper understanding of intercellular crosstalk offer new avenues for developing targeted therapies to restore autolysosomal function, and attenuate neuroinflammation and neurodegeneration.
诸如阿尔茨海默病和帕金森病等神经退行性疾病越来越多地与代谢功能障碍相关，包括肥胖、2型糖尿病和代谢功能障碍相关的脂肪性肝病。这种关联的核心是脂质代谢失调，其不仅影响外周组织，还波及大脑，同时存在自溶酶体功能缺陷、氧化应激、炎症和胰岛素抵抗。脂质占大脑干重的一半以上，在能量供应、结构完整性和突触功能中发挥着关键作用。脂质代谢失调会导致神经炎症、神经元功能受损以及血脑屏障完整性破坏。棕榈酸是高脂饮食中大量存在的饱和脂肪酸，是研究大脑中脂质诱导毒性（脂毒性）的关键模型。棕榈酸会破坏自噬和溶酶体功能、线粒体功能，引发氧化应激，导致神经炎症和神经退行性变。这些影响在神经元中尤为明显，由于其高代谢需求，神经元对脂质诱导的毒性高度敏感。包括星形胶质细胞、小胶质细胞和少突胶质细胞在内的神经胶质细胞，对脂质代谢失调也表现出不同的易损性和适应性反应，进一步加剧神经炎症和脱髓鞘。治疗策略，如补充多不饱和脂肪酸、激活AMP活化蛋白激酶以及靶向溶酶体的干预措施，有望减轻棕榈酸诱导的脂毒性并恢复细胞内稳态。本综述全面研究了棕榈酸诱导的脂毒性及其对包括神经元、星形胶质细胞、小胶质细胞和少突胶质细胞在内的各种中枢神经系统细胞类型自溶酶体功能障碍的影响。此外，还强调了在脂毒性条件下恢复自溶酶体功能的治疗方法。多组学技术的进步以及对细胞间相互作用的更深入理解为开发靶向疗法以恢复自溶酶体功能、减轻神经炎症和神经退行性变提供了新途径。
