Patil Sachin, Sheng Lufang, Masserang Alexis, Chan Christina
Department of Chemical Engineering and Material Science, Michigan State University, East Lansing, MI-48823, USA.
Neurosci Lett. 2006 Oct 2;406(1-2):55-9. doi: 10.1016/j.neulet.2006.07.015. Epub 2006 Aug 9.
High-fat diet is a significant risk factor for the development of Alzheimer's disease (AD). In addition, the AD brain is characterized by elevated levels of fatty acids as compared to that of healthy controls. Despite this, it is unclear how elevated levels of fatty acids are related to the pathogenesis of AD. The present study examines the role of saturated fatty acid, palmitic acid (PA), in causing BACE1 upregulation and consequent amyloidogenic processing of beta-amyloid precursor protein (APP), one of the main characteristic signatures of AD pathology. Here, primary rat cortical neurons and astrocytes were treated with pathological concentration of PA. There was no change in the BACE1 levels in the rat cortical neurons treated directly with PA as compared to controls. The conditioned medium from PA-treated astrocytes, however, caused BACE1 upregulation in the cortical neurons. Moreover, there was a consequent increase in the cleavage of APP leading to the accumulation of the C-terminal fragment of APP (C99) in the cortical neurons. Co-treatment of neurons with 1,3-dimethyl urea (DMU), an antioxidant, decreased PA-induced upregulation in the levels of BACE1 and C99. The present results establish an important role of saturated fatty acids in AD-associated amyloidogenesis through astroglia-mediated oxidative stress.
高脂饮食是阿尔茨海默病（AD）发病的一个重要风险因素。此外，与健康对照相比，AD患者大脑中脂肪酸水平升高。尽管如此，目前尚不清楚脂肪酸水平升高与AD发病机制之间的关系。本研究探讨了饱和脂肪酸棕榈酸（PA）在导致β-分泌酶1（BACE1）上调以及随后β-淀粉样前体蛋白（APP）淀粉样生成过程中的作用，APP淀粉样生成是AD病理学的主要特征之一。在此，用病理浓度的PA处理原代大鼠皮质神经元和星形胶质细胞。与对照组相比，直接用PA处理的大鼠皮质神经元中BACE1水平没有变化。然而，PA处理的星形胶质细胞的条件培养基导致皮质神经元中BACE1上调。此外，APP的裂解随之增加，导致皮质神经元中APP C末端片段（C99）的积累。用抗氧化剂1,3-二甲基脲（DMU）与神经元共同处理，可降低PA诱导的BACE1和C99水平上调。目前的结果表明，饱和脂肪酸通过星形胶质细胞介导的氧化应激在AD相关的淀粉样蛋白生成中起重要作用。
