Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events.
Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events.
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Aβ诱导的突触损伤需要由间接信号事件刺激的CaMKII活性。
DOI：
10.1016/j.isci.2022.104368
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发表时间：
2022-06-17
期刊：
影响因子：
5.8
通讯作者：
Bayer, K. Ulrich
中科院分区：
文献类型：
--
作者：
Brown, Carolyn Nicole;Rumian, Nicole L.;Tullis, Jonathan E.;Coultrap, Steven J.;Bayer, K. Ulrich
Aβ与CaMKII调节结构域具有同源性，并且衍生自该结构域的肽可以结合并破坏CaMKII全酶，这表明Aβ可能具有类似的作用。值得注意的是，Aβ损害由GluN 2B结合介导的突触CaMKII积累，这需要CaMKII组装成全酶。此外，这种Aβ诱导的损伤可通过CaMKII抑制剂预防，CaMKII抑制剂也可抑制推定的直接Aβ结合。然而，我们的研究没有发现Aβ对CaMKII直接影响的任何证据：Aβ在体外没有直接破坏CaMKII全酶、GluN 2B结合、T286自磷酸化或激酶活性。最重要的是，在神经元中，Aβ诱导的CaMKII突触蓄积损伤可被ATP竞争性CaMKII抑制剂阻止，该抑制剂不会干扰假定的直接Aβ结合。总之，我们的研究结果表明，突触Aβ效应不是通过直接结合CaMKII介导的，而是需要通过间接信号传导事件激活CaMKII。Aβ和CaMKII调节结构域共享同源区域Aβ抑制神经元中CaMKII运动需要CaMKII活性Aβ不直接影响CaMKII活性、T286磷酸化或GluN 2B结合因此，Aβ对神经元中CaMKII的作用需要间接信号机制分子神经科学;细胞神经科学
Aβ bears homology to the CaMKII regulatory domain, and peptides derived from this domain can bind and disrupt the CaMKII holoenzyme, suggesting that Aβ could have a similar effect. Notably, Aβ impairs the synaptic CaMKII accumulation that is mediated by GluN2B binding, which requires CaMKII assembly into holoenzymes. Furthermore, this Aβ-induced impairment is prevented by CaMKII inhibitors that should also inhibit the putative direct Aβ binding. However, our study did not find any evidence for direct effects of Aβ on CaMKII: Aβ did not directly disrupt CaMKII holoenzymes, GluN2B binding, T286 autophosphorylation, or kinase activity in vitro. Most importantly, in neurons, the Aβ-induced impairment of CaMKII synaptic accumulation was prevented by an ATP-competitive CaMKII inhibitor that would not interfere with the putative direct Aβ binding. Together, our results indicate that synaptic Aβ effects are not mediated by direct binding to CaMKII, but instead require CaMKII activation via indirect signaling events. Aβ and the CaMKII regulatory domain share a region of homology Suppression of CaMKII movement in neurons by Aβ requires CaMKII activity Aβ does not directly affect CaMKII activity, T286 phosphorylation, or GluN2B binding Thus, the Aβ effects on CaMKII in neurons require indirect signaling mechanisms Molecular neuroscience; Cellular neuroscience
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影响因子：
5
作者：
Neef S;Steffens A;Pellicena P;Mustroph J;Lebek S;Ort KR;Schulman H;Maier LS
通讯作者：
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影响因子：
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通讯作者：
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8.8
作者：
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通讯作者：
Bayer KU