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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms
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Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms

机译：淀粉样蛋白前体蛋白的过表达抑制通过突触前和突触后机制的兴奋性传递。

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摘要

Overexpression of the amyloid precursor protein (APP) in hippocampal neurons leads to elevated P-amyloid peptide (AP) production and consequent depression of excitatory transmission. The precise mechanisms underlying APP-induced synaptic depression are poorly understood. Uncovering these mechanisms could provide insight into how neuronal function is compromised before cell death during the early stages of Alzheimer's disease. Here we verify that APP up-regulation leads to depression of transmission in cultured hippocampal autapses; and we perform whole-cell recording, FM imaging, and immunocytochemistry to identify the specific mechanisms accounting for this depression. We find that APP overexpression leads to postsynaptic silencing through a selective reduction of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated currents. This effect is likely mediated by A beta because expression of mutant APP incapable of producing A beta did not depress transmission. In addition, although we eliminate presynaptic silencing as a mechanism underlying APP-mediated inhibition of transmission, we did observe an A beta-induced presynaptic deficit in vesicle recycling with sustained stimulation. These findings demonstrate that APP elevation disrupts both presynaptic and postsynaptic compartments.
机译：海马神经元中淀粉样蛋白前体蛋白（APP）的过表达导致P-淀粉样肽（AP）产生升高，并因此抑制兴奋性传递。 APP引起的突触抑制的确切机制了解甚少。揭示这些机制可以为深入了解阿尔茨海默氏病早期阶段细胞死亡之前神经元的功能受到损害。在这里，我们证实APP的上调会导致培养的海马突触中传递的抑制。我们进行全细胞记录，FM成像和免疫细胞化学分析，以找出造成这种抑郁症的具体机制。我们发现APP的过表达通过选择性降低α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体介导的电流导致突触后沉默。这种作用可能是由A beta介导的，因为不能产生A beta的突变APP的表达不会抑制传递。另外，尽管我们消除了突触前沉默作为APP介导的抑制传递的基础机制，但我们确实观察到了持续刺激下囊泡回收中Aβ诱导的突触前缺陷。这些发现证明APP的升高同时破坏了突触前和突触后区室。

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