Ratnesh Lal及其同事证明了大多数生物医学研究者认为的对阿兹海默病xx是安全的肽片断可能破坏大脑细胞的神经突，而且可能杀死人类皮层神经元。科学家认为某些聚集形成的（淀粉样）肽通过在细胞膜上形成孔或者通道从而促进了神经疾病，让有毒数量的钙离子进入了神经细胞。更短的非淀粉样肽片断被认为是xx的，它们目前被用于靶向xx阿兹海默病患者。

然而，尽管这些更短的肽已经在神经斑和损伤处发现，这些肽的活动仍然未知。这组作者使用模拟方法和原子力显微镜发现了这些短肽产生了稳定的通道，其宽度足以输送离子，而且进行了额外的测试，表明这些片断与全长度的肽一样，可能破坏或杀死神经突。这组作者说，目前设计用来针对阿兹海默病的非淀粉样路径方法可能需要重新评估。(Bioon.com)

生物谷推荐原文出处：

PNAS doi: 10.1073/pnas.0914251107

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer's Disease and Down syndrome
Hyunbum Janga,1, Fernando Teran Arceb,1,2, Srinivasan Ramachandranb,1,2, Ricardo Caponeb,2, Rushana Azimovac, Bruce L. Kaganc, Ruth Nussinova,d,3, and Ratnesh Lalb,2,3

Full-length amyloid beta peptides (Aβ1–40/42) 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 (Aβ11–42 and Aβ17–42) 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 Aβ9–42 and Aβ17–42 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 Aβ fragments could account for undefined roles played by full length Aβs 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.