Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts
Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts
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DOI：
10.1016/j.neurobiolaging.2006.05.014
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发表时间：
2007-06-01
影响因子：
4.2
通讯作者：
Liguri, Gianfranco
中科院分区：
文献类型：
--
作者：
Cecchi, Cristina;Fiorillo, Claudia;Liguri, Gianfranco
许多实验证据表明，细胞氧化还原状态的失衡是阿尔茨海默病（AD）发病机制的主要因素。我们以前的数据显示，在家族性AD（FAD）患者的原代成纤维细胞膜脂质过氧化显着增加。在本研究中，我们证明了当A β 1-40和A β 1-42的寡聚体结构被添加到培养基中时，它们在质膜附近更快地积累，并且更快地内化，并且主要在APPV 717 I成纤维细胞中比在年龄匹配的健康细胞中内化;这导致活性氧（ROS）的产生更早和更急剧地增加。更高的ROS产生反过来导致膜氧化损伤的增加和细胞抗氧化能力的显著损害，引起凋亡级联激活并最终导致坏死结果。相比之下，健康的成纤维细胞似乎对淀粉样蛋白氧化攻击更具抵抗力，这可能是由于它们的质膜完整性和强大的抗氧化能力。我们的数据是一致的，越来越多的证据表明，prefibrillar聚集体相比，成熟的原纤维，可能是更有毒的物种的肽。这些发现提供了令人信服的证据表明，细胞轴承增加膜脂质过氧化更容易受到聚集毒性，作为其能力降低，以抵消淀粉样蛋白低聚攻击的结果。(c)2006年爱思唯尔公司All rights reserved.
Much experimental evidence suggests that an imbalance in cellular redox status is a major factor in the pathogenesis of Alzheimer's disease (AD). Our previous data showed a marked increase in membrane lipoperoxidation in primary fibroblasts from familial AD (FAD) patients. In the present study, we demonstrate that when oligomeric structures of A beta 1-40 and A beta 1-42 are added to the culture media, they accumulate quicker near the plasma membrane, and are internalized faster and mostly in APPV717I fibroblasts than in age-matched healthy cells; this results in an earlier and sharper increase in the production of reactive oxygen species (ROS). Higher ROS production leads in turn to an increase in membrane oxidative-injury and significant impairment of cellular antioxidant capacity, giving rise to apoptotic cascade activation and finally to a necrotic outcome. In contrast, healthy fibroblasts appear more resistant to amyloid oxidative-attack, possibly as a result of their plasma membrane integrity and powerful antioxidant capacity. Our data are consistent with increasing evidence that prefibrillar aggregates, compared to mature fibrils, are likely the more toxic species of the peptides. These findings provide compelling evidence that cells bearing increased membrane lipoperoxidation are more susceptible to aggregate toxicity as a result of their reduced ability to counteract amyloid oligomeric attack. (c) 2006 Elsevier Inc. All rights reserved.