PDF(Pubmed)
Abstract：
Presenilin 1 (PS1) is a transmembrane proteolytic subunit of γ-secretase that cleaves amyloid precursor proteins. Mutations in PS1 (mPS1) are associated with early-onset familial Alzheimer\'s disease (AD). The link between mutated PS1, mitochondrial calcium regulation, and AD has been studied extensively in different test systems. Despite the wide-ranging role of mPS1 in AD, there is a paucity of information on the link between PS1 and neuronal cell death, a hallmark of AD. In the present study, we employed the selective mitochondrial uncoupler carbonyl cyanide chlorophenylhydrazone (CCCP) and compared the reactivity of mPS1-transfected cultured rat hippocampal neurons with PS1 and control neurons in a situation of impaired mitochondrial functions. CCCP causes a slow rise in cytosolic and mitochondrial calcium in all three groups of neurons, with the mPS1 neurons demonstrating a faster rise. Consequently, mPS1 neurons were depolarized by CCCP and measured with TMRM, a mitochondrial voltage indicator, more than the other two groups. Morphologically, CCCP produced more filopodia in mPS1 neurons than in the other two groups, which were similarly affected by the drug. Finally, mPS1 transfected neurons tended to die from prolonged exposure to CCCP sooner than the other groups, indicating an increase in vulnerability associated with a lower ability to regulate excess cytosolic calcium.
摘要：
早老素1（PS1）是γ-分泌酶的跨膜蛋白水解亚基，可裂解淀粉样蛋白前体蛋白。PS1(mPS1)突变与早发性家族性阿尔茨海默病(AD)相关。突变的PS1，线粒体钙调节之间的联系，和AD已经在不同的测试系统中进行了广泛的研究。尽管mPS1在AD中的作用广泛，关于PS1和神经元细胞死亡之间联系的信息很少，AD的标志。在本研究中,我们使用了选择性线粒体解偶联剂羰基氰化物氯苯腙（CCCP），并比较了mPS1转染的培养大鼠海马神经元与PS1和对照神经元在线粒体功能受损情况下的反应性。CCCP引起所有三组神经元的胞浆和线粒体钙的缓慢升高，mPS1神经元表现出更快的上升。因此,mPS1神经元通过CCCP去极化并用TMRM测量，线粒体电压指示器,超过其他两组。形态学上,CCCP在mPS1神经元中产生的丝状伪足多于其他两组，同样受到药物的影响。最后,mPS1转染的神经元倾向于死于长期暴露于CCCP比其他组，表明与调节过量胞质钙的能力降低相关的脆弱性增加。
