Time-dependent reversal of synaptic plasticity induced by physiological concentrations of oligomeric Aβ42: an early index of Alzheimer's disease.
Time-dependent reversal of synaptic plasticity induced by physiological concentrations of oligomeric Aβ42: an early index of Alzheimer's disease.
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DOI：
10.1038/srep32553
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发表时间：
2016-09-01
影响因子：
4.6
通讯作者：
Arancio O
中科院分区：
文献类型：
--
作者：
Koppensteiner P;Trinchese F;Fà M;Puzzo D;Gulisano W;Yan S;Poussin A;Liu S;Orozco I;Dale E;Teich AF;Palmeri A;Ninan I;Boehm S;Arancio O
寡聚淀粉样β（Aβ）肽被认为通过引起突触功能障碍而导致阿尔茨海默病（AD）的细微遗忘改变。在这里，我们研究了小鼠海马神经元暴露于皮摩尔浓度的Aβ42后突触变化的时间过程，模拟其在大脑中的生理水平。我们发现，短时间暴露在几分钟内可增强突触可塑性，而长时间暴露持续几小时则会降低突触可塑性。可塑性降低伴随着自发神经递质释放的基础频率增加，功能性突触前释放位点的基础数量增加，以及突触蛋白的重新分布，包括囊泡相关蛋白突触素I，突触素，和突触后谷氨酸受体I这些突触的改变介导的细胞骨架的变化，涉及肌动蛋白聚合和p38丝裂原活化蛋白激酶。这些体外研究结果在体内实验中得到了证实，海马短时间输注皮摩尔Aβ可增强背景记忆，而长时间输注则会损害背景记忆。我们的研究结果提供了一种突触功能障碍的起始模型，即长时间暴露于生理水平的Aβ可导致突触的微结构变化，从而导致递质释放增加、突触可塑性丧失和记忆丧失。
The oligomeric amyloid-β (Aβ) peptide is thought to contribute to the subtle amnesic changes in Alzheimer’s disease (AD) by causing synaptic dysfunction. Here, we examined the time course of synaptic changes in mouse hippocampal neurons following exposure to Aβ42 at picomolar concentrations, mimicking its physiological levels in the brain. We found opposite effects of the peptide with short exposures in the range of minutes enhancing synaptic plasticity, and longer exposures lasting several hours reducing it. The plasticity reduction was concomitant with an increase in the basal frequency of spontaneous neurotransmitter release, a higher basal number of functional presynaptic release sites, and a redistribution of synaptic proteins including the vesicle-associated proteins synapsin I, synaptophysin, and the post-synaptic glutamate receptor I. These synaptic alterations were mediated by cytoskeletal changes involving actin polymerization and p38 mitogen-activated protein kinase. These in vitro findings were confirmed in vivo with short hippocampal infusions of picomolar Aβ enhancing contextual memory and prolonged infusions impairing it. Our findings provide a model for initiation of synaptic dysfunction whereby exposure to physiologic levels of Aβ for a prolonged period of time causes microstructural changes at the synapse which result in increased transmitter release, failure of synaptic plasticity, and memory loss.
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影响因子：
2.5
作者：
DELAERE, P;DUYCKAERTS, C;HAUW, JJ
通讯作者：
HAUW, JJ
影响因子：
16.2
作者：
Kamenetz, F;Tomita, T;Malinow, R
通讯作者：
Malinow, R
影响因子：
2.5
作者：
Giedraitis, Vilmantas;Sundelof, Johan;Lannfelt, Lars
通讯作者：
Lannfelt, Lars
影响因子：
9.9
作者：
ARRIAGADA, PV;GROWDON, JH;HYMAN, BT
通讯作者：
HYMAN, BT
影响因子：
5.3
作者：
Lawrence, James L. M.;Tong, Mei;Nichols, Robert A.
通讯作者：
Nichols, Robert A.