Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo
Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo
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DOI：
10.1038/416535a
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发表时间：
2002-04-04
期刊：
影响因子：
64.8
通讯作者：
Selkoe, DJ
中科院分区：
文献类型：
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作者：
Walsh, DM;Klyubin, I;Selkoe, DJ
尽管大量数据支持淀粉样β蛋白（Abeta）在阿尔茨海默病中的主要致病作用（1），但淀粉样蛋白假说仍然存在争议，部分原因是Abeta的特定神经毒性种类及其对突触功能的影响性质尚未在体内确定。在这里，我们报告说，天然寡聚体的人Abeta肽生成后不久，在特定的细胞内囊泡，并随后从细胞分泌。脑显微注射含有这些寡聚体和丰富的Abeta单体，但没有淀粉样纤维的细胞培养基显着抑制海马长时程增强（LTP）在大鼠体内。从所有抗体种类的介质中的免疫耗竭完全废除了这种效果。用胰岛素降解酶预处理培养基，该酶降解Abeta单体但不降解寡聚体，并不能阻止LTP的抑制。因此，在不存在单体和淀粉样纤维的情况下，Abeta低聚物在人脑和脑脊液中发现的浓度下会破坏体内突触可塑性。最后，用γ-分泌酶抑制剂处理细胞在允许可观的单体产生的剂量下防止了寡聚体形成，并且这种介质不再破坏LTP，表明突触毒性Abeta寡聚体可以在治疗上靶向。
Although extensive data support a central pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease(1), the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Abeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Abeta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Abeta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Ab species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Abeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Abeta oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic Abeta oligomers can be targeted therapeutically.