Physiological Concentrations of Amyloid Beta Regulate Recycling of Synaptic Vesicles via Alpha7 Acetylcholine Receptor and CDK5/Calcineurin Signaling.
Physiological Concentrations of Amyloid Beta Regulate Recycling of Synaptic Vesicles via Alpha7 Acetylcholine Receptor and CDK5/Calcineurin Signaling.
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DOI：
10.3389/fnmol.2017.00221
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发表时间：
2017
影响因子：
4.8
通讯作者：
Fejtova A
中科院分区：
文献类型：
--
作者：
Lazarevic V;Fieńko S;Andres-Alonso M;Anni D;Ivanova D;Montenegro-Venegas C;Gundelfinger ED;Cousin MA;Fejtova A
尽管淀粉样β（Aβ）肽在阿尔茨海默病（AD）的发病机制中起着重要作用，但其在健康脑中的生理功能仍存在争议。已经确定，Aβ水平升高可诱导突触抑制和解体，与神经毒性和神经元丢失相关。越来越多的证据表明Aβ对突触功能和认知具有积极的调节作用;然而，确切的细胞和分子相关性仍不清楚。在这项工作中，我们测试了生理浓度的内源性Aβ物质对在分离培养物中生长的大鼠皮层和海马神经元中神经递质释放的影响。调节内源性Aβ物质的产生和降解以及应用合成啮齿类动物Aβ40和Aβ42影响个体突触前神经递质释放的功效。低皮摩尔浓度的Aβ40和Aβ42增加，而Aβ耗竭或应用低微摩尔浓度的A β减少突触囊泡的再循环，显示Aβ对神经递质释放的兴奋效应。这些Aβ介导的调节需要功能性α 7乙酰胆碱受体以及细胞外和细胞内钙，涉及CDK 5和钙调神经磷酸酶信号传导的调节以及突触囊泡再循环的增加。这些数据表明，Aβ调节突触前神经递质的释放，并表明Aβ在SV循环微调中的正常生理功能的失败可能会破坏突触功能和稳态，最终导致认知能力下降和神经退行性变。
Despite the central role of amyloid β (Aβ) peptide in the etiopathogenesis of Alzheimer’s disease (AD), its physiological function in healthy brain is still debated. It is well established that elevated levels of Aβ induce synaptic depression and dismantling, connected with neurotoxicity and neuronal loss. Growing evidence suggests a positive regulatory effect of Aβ on synaptic function and cognition; however the exact cellular and molecular correlates are still unclear. In this work, we tested the effect of physiological concentrations of Aβ species of endogenous origin on neurotransmitter release in rat cortical and hippocampal neurons grown in dissociated cultures. Modulation of production and degradation of the endogenous Aβ species as well as applications of the synthetic rodent Aβ40 and Aβ42 affected efficacy of neurotransmitter release from individual presynapses. Low picomolar Aβ40 and Aβ42 increased, while Aβ depletion or application of low micromolar concentration decreased synaptic vesicle recycling, showing a hormetic effect of Aβ on neurotransmitter release. These Aβ-mediated modulations required functional alpha7 acetylcholine receptors as well as extracellular and intracellular calcium, involved regulation of CDK5 and calcineurin signaling and increased recycling of synaptic vesicles. These data indicate that Aβ regulates neurotransmitter release from presynapse and suggest that failure of the normal physiological function of Aβ in the fine-tuning of SV cycling could disrupt synaptic function and homeostasis, which would, eventually, lead to cognitive decline and neurodegeneration.
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影响因子：
16.2
作者：
Kim, Sung Hyun;Ryan, Timothy A.
通讯作者：
Ryan, Timothy A.
DOI：
10.1083/jcb.200807155
发表时间：
2009-04-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fejtova A;Davydova D;Bischof F;Lazarevic V;Altrock WD;Romorini S;Schöne C;Zuschratter W;Kreutz MR;Garner CC;Ziv NE;Gundelfinger ED
通讯作者：
Gundelfinger ED
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
5.3
作者：
Hurst, RS;Hajós, M;Arneric, SP
通讯作者：
Arneric, SP
影响因子：
16.2
作者：
Kamenetz, F;Tomita, T;Malinow, R
通讯作者：
Malinow, R