Mechanisms of tau and Aβ-induced excitotoxicity.
Mechanisms of tau and Aβ-induced excitotoxicity.
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DOI：
10.1016/j.brainres.2015.12.048
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发表时间：
2016-03-01
期刊：
影响因子：
2.9
通讯作者：
Johnson GVW
中科院分区：
文献类型：
--
作者：
Pallo SP;DiMaio J;Cook A;Nilsson B;Johnson GVW
兴奋性毒性最初被假定为阿尔茨海默病（AD）相关神经退行性变的晚期副作用，但最近的研究表明，它可能发生在AD的早期，并有助于神经退行性变过程。Tau和淀粉样蛋白β（Aβ）是神经元缠结（NFT）和淀粉样蛋白斑块的主要成分，它们协同或独立地促进兴奋性毒性。我们的研究探讨了tau和Aβ在AD相关兴奋毒性中的作用。体内研究表明，tau基因敲除（tau−/−）小鼠可显著防止谷氨酸类似物红藻氨酸（KA）诱导的癫痫发作和海马超氧化物产生。我们假设tau通过促进KA诱导的Ca 2+流入神经元来实现这一点，然而慢病毒tau敲低未能改善KA诱导的Ca 2+流入原代大鼠皮层神经元。我们进一步研究了tau是否与Aβ协同促进KA诱导的Ca 2+内流。虽然Aβ双相调节KA诱导的Ca 2 +cyt反应，但tau敲低仍然没有影响。因此，tau蛋白促进KA诱导的癫痫发作和超氧化物产生的方式，不涉及通过KA受体（KAR）促进Ca 2+内流。另一方面，Aβ急性预处理（10分钟）增强KA诱导的Ca 2+内流，而慢性Aβ（24小时）显著降低了Ca 2+内流，与tau敲低无关。鉴于先前发表的Aβ、1组代谢型谷氨酸受体（mGluRs）和KAR调节之间的联系，我们假设Aβ通过1组mGluRs介导的G蛋白偶联受体途径调节KAR。我们发现，Aβ不激活第1组mGluRs，抑制这些受体并不能逆转Aβ对KA诱导的Ca 2+内流的调节。因此，Aβ通过不涉及1型mGluR激活的机制双相调节KAR。
Excitotoxicity was originally postulated to be a late stage side effect of Alzheimer’s disease (AD)-related neurodegeneration, however more recent studies indicate that it may occur early in AD and contribute to the neurodegenerative process. Tau and amyloid beta (Aβ), the main components of neurofibrillary tangles (NFTs) and amyloid plaques, have been implicated in cooperatively and independently facilitating excitotoxicity. Our study investigated the roles of tau and Aβ in AD-related excitotoxicity. In vivo studies showed that tau knockout (tau−/−) mice were significantly protected from seizures and hippocampal superoxide production induced with the glutamate analog, kainic acid (KA). We hypothesized that tau accomplished this by facilitating KA-induced Ca2+ influx into neurons, however lentiviral tau knockdown failed to ameliorate KA-induced Ca2+ influx into primary rat cortical neurons. We further investigated if tau cooperated with Aβ to facilitate KA-induced Ca2+ influx. While Aβ biphasically modulated the KA-induced Ca2+cyt responses, tau knockdown continued to have no effect. Therefore, tau facilitates KA-induced seizures and superoxide production in a manner that does not involve facilitation of Ca2+ influx through KA receptors (KAR). On the other hand, acute pretreatment with Aβ (10 minutes) enhanced KA-induced Ca2+ influx, while chronic Aβ (24 hours) significantly reduced it, regardless of tau knockdown. Given previously published connections between Aβ, group 1 metabotropic glutamate receptors (mGluRs), and KAR regulation, we hypothesized that Aβ modulates KAR via a G-protein coupled receptor pathway mediated by group 1 mGluRs. We found that Aβ did not activate group 1 mGluRs and inhibition of these receptors did not reverse Aβ modulation of KA-induced Ca2+ influx. Therefore, Aβ biphasically regulates KAR via a mechanism that does not involve group 1 mGluR activation.