阿尔茨海默病（AD）是最常见的痴呆症病因，全球超过1500万人受其影响。传统观点认为，β淀粉样蛋白（Aβ）斑块是AD的主要致病因素。然而，近期来自加州大学圣地亚哥分校等机构的研究人员发现，一种更小的非淀粉样肽片段可能通过破坏大脑细胞的神经突，杀死人类皮层神经元，从而在疾病进程中扮演关键角色。这一研究成果发表在《PNAS》杂志上。

领导这项研究的是加州大学圣地亚哥分校的Ratnesh Lal博士，他长期从事阿尔茨海默病研究，曾发明突破性方法以更好地研究AD、亨廷顿病和帕金森病等退行性疾病中的脑细胞退化情况。

该研究从β淀粉样肽入手，揭示了细胞膜中错误折叠的蛋白质及其导致的细胞电学特征变化是细胞退化的原因。错误折叠蛋白的特定三维结构被埋藏在细胞膜中。长期以来，人们认为淀粉样斑块是AD的直接病因，但新研究证明斑块并非直接原因，因为斑块纤维太大，无法直接影响小细胞。相反，问题可能在于细胞膜中的小团畸形、错误折叠的蛋白。

在最新研究中，研究人员证明，大多数生物医学研究者认为对AD治疗安全的肽片段可能破坏大脑细胞的神经突，甚至杀死人类皮层神经元。他们认为，某些聚集形成的淀粉样肽通过在细胞膜上形成孔或通道，促进神经疾病，让有毒数量的钙离子进入神经细胞。

这一发现改进了淀粉样蛋白假说，提示神经退行性变可能是由形成斑块的大肽的较小Aβ片段引起的。研究结果显示，最小的非淀粉样蛋白源性肽可能是Aβ假说中最重要的部分。

更短的非淀粉样肽片段曾被认为无毒，目前被用于靶向治疗AD患者。然而，尽管这些短肽已在神经斑和损伤处被发现，其活性仍未知。研究人员利用模拟方法和原子力显微镜发现，这些短肽产生了稳定的通道，其宽度足以输送离子。进一步测试表明，这些片段与全长肽一样，可能破坏或杀死神经突。

这一发现可能对理解靶向减少全长β淀粉样肽（Aβ1-40/42）的AD治疗药物的局限性有所帮助。Aβ1-40/42形成在AD患者中可见的脑部斑块，并被认为是AD的可能病因。上述药物在减少Aβ1-40/42数量的同时，也会增加短肽的数量，从而抵消药物治疗的益处，并促进AD的自然进展。

原文检索：Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer's Disease and Down syndrome

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.