Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid-β1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model
Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid-β1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model
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DOI：
10.1523/jneurosci.5901-11.2012
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发表时间：
2012-06-06
影响因子：
5.3
通讯作者：
Buee, Luc
中科院分区：
文献类型：
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作者：
Brouillette, Jonathan;Caillierez, Raphaelle;Buee, Luc
神经元和突触变性是阿尔茨海默病(AD)记忆衰退的最好的病理相关因素。尽管低分子量淀粉样蛋白-β(A-beta)寡聚体的积累被认为是引发AD神经变性的因素，但过度表达或注入A-β的动物模型在记忆障碍开始时缺乏神经元的丢失。利用一种新的体内方法，我们发现，在清醒的自由活动小鼠的海马区重复注射小的可溶性Aβ(1-42)寡聚体能够诱导显著的神经元丢失、tau过度磷酸化和海马区依赖记忆的缺陷。在体内和体外观察到小Aβ(1-42)物种的神经毒性与caspase-3活性增加和NMDA受体亚单位NR2B水平降低有关。我们发现，隔离剂反式甲状腺素能够结合有毒的Aβ(1-42)物种，并减轻神经元的损失和记忆障碍。我们新的小鼠模型提供了证据，表明小的、可溶的Aβ(1-42)寡聚体能够在体内诱导广泛的神经元丢失，并启动一系列模仿AD关键神经病理特征的事件。
Neuronal and synaptic degeneration are the best pathological correlates for memory decline in Alzheimer's disease (AD). Although the accumulation of soluble low-molecular-weight amyloid-beta (A beta) oligomers has been suggested to trigger neurodegeneration in AD, animal models overexpressing or infused with A beta lack neuronal loss at the onset of memory deficits. Using a novel in vivo approach, we found that repeated hippocampal injections of small soluble A beta(1-42) oligomers in awake, freely moving mice were able to induce marked neuronal loss, tau hyperphosphorylation, and deficits in hippocampus-dependent memory. The neurotoxicity of small A beta(1-42) species was observed in vivo as well as in vitro in association with increased caspase-3 activity and reduced levels of the NMDA receptor subunit NR2B. We found that the sequestering agent transthyretin is able to bind the toxic A beta(1-42) species and attenuated the loss of neurons and memory deficits. Our novel mouse model provides evidence that small, soluble A beta(1-42) oligomers are able to induce extensive neuronal loss in vivo and initiate a cascade of events that mimic the key neuropathological hallmarks of AD.