Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc, National Cancer Institute, Frederick, MD 21702, USA.
Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6538-43. doi: 10.1073/pnas.0914251107. Epub 2010 Mar 22.
Full-length amyloid beta peptides (Abeta(1-40/42)) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. However, recent transgenic animal models cast doubt on their direct role in AD pathology. Nonamyloidogenic truncated amyloid-beta fragments (Abeta(11-42) and Abeta(17-42)) are also found in amyloid plaques of AD and in the preamyloid lesions of Down syndrome, a model system for early-onset AD study. Very little is known about the structure and activity of these smaller peptides, although they could be the primary AD and Down syndrome pathological agents. Using complementary techniques of molecular dynamics simulations, atomic force microscopy, channel conductance measurements, calcium imaging, neuritic degeneration, and cell death assays, we show that nonamyloidogenic Abeta(9-42) and Abeta(17-42) peptides form ion channels with loosely attached subunits and elicit single-channel conductances. The subunits appear mobile, suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in amyloid precursor protein-deficient cells. The channel mediated calcium uptake induces neurite degeneration in human cortical neurons. Channel conductance, calcium uptake, and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus, truncated Abeta fragments could account for undefined roles played by full length Abetas and provide a unique mechanism of AD and Down syndrome pathologies. The toxicity of nonamyloidogenic peptides via an ion channel mechanism necessitates a reevaluation of the current therapeutic approaches targeting the nonamyloidogenic pathway as avenue for AD treatment.
全长淀粉样β肽（Abeta（1-40/42））在阿尔茨海默病（AD）患者中形成神经原纤维缠结淀粉样斑块，并与 AD 病理学有关。然而，最近的转基因动物模型对它们在 AD 病理学中的直接作用提出了质疑。非淀粉样生成的截断淀粉样β片段（Abeta（11-42）和 Abeta（17-42））也存在于 AD 的淀粉样斑块中和唐氏综合征的淀粉样前病变中，唐氏综合征是研究早发性 AD 的模型系统。尽管这些较小的肽可能是 AD 和唐氏综合征的主要病理因子，但对于它们的结构和活性知之甚少。使用分子动力学模拟、原子力显微镜、通道电导测量、钙成像、神经原纤维变性和细胞死亡测定等互补技术，我们表明非淀粉样生成的 Abeta（9-42）和 Abeta（17-42）肽形成具有松散附着亚基的离子通道，并引起单通道电导。亚基似乎是可移动的，表明插入了小寡聚物，随后是动态通道组装和解离。这些通道允许在淀粉样前体蛋白缺陷细胞中摄取钙。通道介导的钙摄取诱导人皮质神经元的神经原纤维变性。通道电导、钙摄取和神经原纤维变性可被锌选择性抑制，锌是淀粉样通道活性的阻断剂。因此，截断的 Abeta 片段可以解释全长 Abetas 所扮演的未定义角色，并为 AD 和唐氏综合征的病理学提供独特的机制。通过离子通道机制发挥毒性的非淀粉样生成肽需要重新评估当前针对非淀粉样生成途径的治疗方法，因为这是 AD 治疗的一种途径。
