Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang 050017, China.
Neurosci Lett. 2012 Oct 18;528(1):6-10. doi: 10.1016/j.neulet.2012.08.086. Epub 2012 Sep 7.
Alzheimer's disease (AD) is characterized by the accumulation of the β-amyloid peptide (Aβ), which is generated from sequential cleavages of the amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. Fatty acid alterations in AD brains have recently received substantial attention. Because increased very long chain fatty acid (VLCFA) levels in AD brains imply that peroxisomal β-oxidation dysfunction may be associated with AD pathogenesis, we investigated the effects of impaired peroxisomal β-oxidation on Aβ generation in vivo and in vitro using thioridazine, a selective peroxisomal β-oxidation inhibitor. Under the experimental conditions, thioridazine caused VLCFA accumulation and increases in Aβ(40) content, APP immunoreactivity and APP(751+770) mRNA expressions in the rat cerebral cortex. A correlation analysis showed that the Aβ(40) levels were positively correlated with the cortex C(24:0) and C(26:0) levels. Additionally, the primary cerebral cortex neurons treated with this compound showed increases in APP(751+770) mRNA, APP protein, BACE1 mRNA and protein, and secreted Aβ40 levels. This work supports an emerging viewpoint that impaired peroxisomal function may play an important role in the progression of AD pathology.
阿尔茨海默病（AD）的特征是β-淀粉样肽（Aβ）的积累，Aβ由淀粉样前体蛋白（APP）通过β-分泌酶（BACE1）和γ-分泌酶的顺序切割产生。AD 大脑中的脂肪酸改变最近受到了广泛关注。由于 AD 大脑中非常长链脂肪酸（VLCFA）水平的增加意味着过氧化物酶体β-氧化功能障碍可能与 AD 发病机制有关，因此我们使用噻氯匹定（一种选择性过氧化物酶体β-氧化抑制剂）研究了过氧化物酶体β-氧化受损对体内和体外 Aβ生成的影响。在实验条件下，噻氯匹定导致大鼠大脑皮质 VLCFA 积累和 Aβ（40）含量、APP 免疫反应性和 APP（751+770）mRNA 表达增加。相关性分析表明，Aβ（40）水平与皮质 C（24：0）和 C（26：0）水平呈正相关。此外，用该化合物处理的原代大脑皮质神经元显示 APP（751+770）mRNA、APP 蛋白、BACE1 mRNA 和蛋白以及分泌的 Aβ40 水平增加。这项工作支持了一种新出现的观点，即过氧化物酶体功能受损可能在 AD 病理进展中发挥重要作用。
