Aβ Oligomers Cause Localized Ca2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines
Aβ Oligomers Cause Localized Ca2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines
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DOI：
10.1523/jneurosci.2357-10.2010
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发表时间：
2010-09
期刊：
影响因子：
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通讯作者：
H. Zempel;E. Thies;E. Mandelkow;E. Mandelkow
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文献类型：
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作者：
H. Zempel;E. Thies;E. Mandelkow;E. Mandelkow
β淀粉样蛋白（Aβ）和Tau蛋白的聚集是阿尔茨海默病（AD）的标志，根据Aβ级联假说，认为Aβ对神经元具有毒性，Tau是Aβ的下游靶点。我们研究了分化的原代海马神经元暴露于Aβ寡聚体后的早期局部变化。与正常神经元中的轴突分选相反，内源性Tau进入体树突隔室的误分选使初始事件变得明显。在错误排序的树枝状区域中，棘被耗尽，Ca 2+局部增加，微管被破坏。这些区域中的Tau在诊断AD-Tau的某些位点（例如，抗体12 E8的表位，其磷酸化导致Tau从微管上脱离，和AT 8表位），和某些激酶活性的局部升高（例如，MARK/par-1、BRSK/SADK、p70S6K、cdk5，而非GSK 3 β、JNK、MAPK）。这些局部效应发生时，Tau、微管蛋白或激酶水平没有整体变化。体树错配不仅发生在Tau身上，也发生在其他轴突蛋白如神经丝上，并与微管和线粒体的明显缺失相关。紫杉醇可阻止Aβ诱导的微管和线粒体耗竭、Tau分选错误和棘丢失效应，表明Aβ诱导的微管不稳定和相应的交通缺陷是早期变性的关键因素。相反，Ca 2+水平、激酶活性和Tau磷酸化的升高不能被紫杉醇阻止。与Aβ寡聚体相似的初期和局部变化可以由细胞应激源诱发（例如，H2 O2，谷氨酸，血清剥夺），提示一些共同的信号传导机制。
Aggregation of amyloid-β (Aβ) and Tau protein are hallmarks of Alzheimer's disease (AD), and according to the Aβ-cascade hypothesis, Aβ is considered toxic for neurons and Tau a downstream target of Aβ. We have investigated differentiated primary hippocampal neurons for early localized changes following exposure to Aβ oligomers. Initial events become evident by missorting of endogenous Tau into the somatodendritic compartment, in contrast to axonal sorting in normal neurons. In missorted dendritic regions there is a depletion of spines and local increase in Ca2+, and breakdown of microtubules. Tau in these regions shows elevated phosphorylation at certain sites diagnostic of AD-Tau (e.g., epitope of antibody 12E8, whose phosphorylation causes detachment of Tau from microtubules, and AT8 epitope), and local elevation of certain kinase activities (e.g., MARK/par-1, BRSK/SADK, p70S6K, cdk5, but not GSK3β, JNK, MAPK). These local effects occur without global changes in Tau, tubulin, or kinase levels. Somatodendritic missorting occurs not only with Tau, but also with other axonal proteins such as neurofilaments, and correlates with pronounced depletion of microtubules and mitochondria. The Aβ-induced effects on microtubule and mitochondria depletion, Tau missorting, and loss of spines are prevented by taxol, indicating that Aβ-induced microtubule destabilization and corresponding traffic defects are key factors in incipient degeneration. By contrast, the rise in Ca2+ levels, kinase activities, and Tau phosphorylation cannot be prevented by taxol. Incipient and local changes similar to those of Aβ oligomers can be evoked by cell stressors (e.g., H2O2, glutamate, serum deprivation), suggesting some common mechanism of signaling.