Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins
Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins
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DOI：
10.1073/pnas.95.11.6448
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发表时间：
1998-05-26
影响因子：
11.1
通讯作者：
Klein, WL
中科院分区：
文献类型：
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作者：
Lambert, MP;Barlow, AK;Klein, WL
A β（1-42）是一种自缔合肽，其神经毒性衍生物被认为在阿尔茨海默病的发病机制中起作用。淀粉样β蛋白（A β）的神经毒性已归因于其纤维形式，但这里提出的实验表征了当纤维形成受到抑制时聚集的神经毒素。这些神经毒素包含小的可扩散的A β寡聚体（对于A β衍生的可扩散配体，称为ADDL），发现其在纳摩尔浓度下杀死器官型中枢神经系统培养物中的成熟神经元。在细胞表面，ADDL结合到胰蛋白酶敏感位点，表面衍生的胰蛋白酶肽阻断结合并提供神经保护。Fyn是一种与细胞凋亡相关的蛋白酪氨酸激酶，在阿尔茨海默病中升高，Fyn的种系敲除也具有神经保护作用。值得注意的是，ADDL诱发的神经功能障碍早在细胞变性之前就发生了。没有滞后，尽管保留诱发动作电位，ADDLs抑制海马长时程增强，表明对信号转导的直接影响。我们推测，受损的突触可塑性和相关的记忆功能障碍，在早期阶段阿尔茨海默氏病和严重的细胞变性和痴呆症在终末期可能是由双相影响的A β衍生的扩散配体作用于特定的神经信号转导通路。
A beta(1-42) is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer's pathogenesis. Neurotoxicity of amyloid beta protein (A beta) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible A beta oligomers (referred to as ADDLs, for A beta-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer's disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of A beta-derived diffusible ligands acting upon particular neural signal transduction pathways.