Synaptic targeting by Alzheimer's-related amyloid beta oligomers.
Synaptic targeting by Alzheimer's-related amyloid beta oligomers.
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发表时间：
2004
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通讯作者：
P. Lacor;Maria C. F. Buniel;Lei Chang;Sara J. Fernandez;Yuesong Gong;K. Viola;M. Lambert;P. Velasco;E. Bigio;C. Finch;G. Krafft;W. Klein
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作者：
P. Lacor;Maria C. F. Buniel;Lei Chang;Sara J. Fernandez;Yuesong Gong;K. Viola;M. Lambert;P. Velasco;E. Bigio;C. Finch;G. Krafft;W. Klein
早期阿尔茨海默病 (AD) 的认知标志是极其无法形成新记忆。多年来，这种痴呆症被认为是由纤维状淀粉样β蛋白（Abeta）沉积引起的神经细胞死亡所致。然而，一个新的假说已经出现，其中早期记忆丧失被认为是由可溶性 Abeta 寡聚物引起的突触故障。这种寡聚体会迅速阻断长时程增强，这是突触可塑性的经典实验范式，并且它们在 AD 脑组织和转基因小鼠 AD 模型中显着升高。目前的工作描述了 Abeta 寡聚物攻击神经元的方式。发现针对应用于 AD 脑切片的合成寡聚物产生的抗体在神经元细胞体周围产生弥漫性染色，表明存在树突模式，而可溶性脑提取物在点免疫印迹中显示出强烈的 AD 依赖性反应性。未分级的 AD 提取物中的抗原特异性地附着在培养的大鼠海马神经元上，在离散点的树突乔木内结合。粗分级显示配体大小在 10 至 100 kDa 之间。相同大小的合成 Abeta 寡聚物具有相同的点状结合，这对特定神经元具有高度选择性。通过共焦双标记免疫荧光图像分析确定，>90% 的点状寡聚物结合位点与突触标记 PSD-95（突触后密度蛋白 95）共定位。突触结合伴随着 Arc 的异位诱导，Arc 是一种突触立即早期基因，其过度表达与学习功能障碍有关。结果表明，Abeta 寡聚物对特定突触的靶向和功能破坏可能为早期 AD 中记忆功能的特定丧失提供分子基础。
The cognitive hallmark of early Alzheimer's disease (AD) is an extraordinary inability to form new memories. For many years, this dementia was attributed to nerve-cell death induced by deposits of fibrillar amyloid beta (Abeta). A newer hypothesis has emerged, however, in which early memory loss is considered a synapse failure caused by soluble Abeta oligomers. Such oligomers rapidly block long-term potentiation, a classic experimental paradigm for synaptic plasticity, and they are strikingly elevated in AD brain tissue and transgenic-mouse AD models. The current work characterizes the manner in which Abeta oligomers attack neurons. Antibodies raised against synthetic oligomers applied to AD brain sections were found to give diffuse stain around neuronal cell bodies, suggestive of a dendritic pattern, whereas soluble brain extracts showed robust AD-dependent reactivity in dot immunoblots. Antigens in unfractionated AD extracts attached with specificity to cultured rat hippocampal neurons, binding within dendritic arbors at discrete puncta. Crude fractionation showed ligand size to be between 10 and 100 kDa. Synthetic Abeta oligomers of the same size gave identical punctate binding, which was highly selective for particular neurons. Image analysis by confocal double-label immunofluorescence established that >90% of the punctate oligomer binding sites colocalized with the synaptic marker PSD-95 (postsynaptic density protein 95). Synaptic binding was accompanied by ectopic induction of Arc, a synaptic immediate-early gene, the overexpression of which has been linked to dysfunctional learning. Results suggest the hypothesis that targeting and functional disruption of particular synapses by Abeta oligomers may provide a molecular basis for the specific loss of memory function in early AD.