De Felice Fernanda G, Wu Diana, Lambert Mary P, Fernandez Sara J, Velasco Pauline T, Lacor Pascale N, Bigio Eileen H, Jerecic Jasna, Acton Paul J, Shughrue Paul J, Chen-Dodson Elizabeth, Kinney Gene G, Klein William L
Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA.
Neurobiol Aging. 2008 Sep;29(9):1334-47. doi: 10.1016/j.neurobiolaging.2007.02.029. Epub 2007 Apr 2.
Alzheimer's disease (AD) is characterized by presence of extracellular fibrillar A beta in amyloid plaques, intraneuronal neurofibrillary tangles consisting of aggregated hyperphosphorylated tau and elevated brain levels of soluble A beta oligomers (ADDLs). A major question is how these disparate facets of AD pathology are mechanistically related. Here we show that, independent of the presence of fibrils, ADDLs stimulate tau phosphorylation in mature cultures of hippocampal neurons and in neuroblastoma cells at epitopes characteristically hyperphosphorylated in AD. A monoclonal antibody that targets ADDLs blocked their attachment to synaptic binding sites and prevented tau hyperphosphorylation. Tau phosphorylation was blocked by the Src family tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4-D)pyramide (PP1), and by the phosphatidylinositol-3-kinase inhibitor LY294002. Significantly, tau hyperphosphorylation was also induced by a soluble aqueous extract containing A beta oligomers from AD brains, but not by an extract from non-AD brains. A beta oligomers have been increasingly implicated as the main neurotoxins in AD, and the current results provide a unifying mechanism in which oligomer activity is directly linked to tau hyperphosphorylation in AD pathology.
阿尔茨海默病（AD）的特征是在淀粉样斑块中存在细胞外纤维状β淀粉样蛋白（Aβ）、由聚集的高度磷酸化tau蛋白组成的神经元内神经原纤维缠结以及脑内可溶性Aβ寡聚体（ADDLs）水平升高。一个主要问题是AD病理学的这些不同方面在机制上是如何相关的。在此我们表明，与纤维的存在无关，ADDLs在海马神经元成熟培养物和神经母细胞瘤细胞中刺激tau蛋白在AD中特征性高度磷酸化的表位处发生磷酸化。一种靶向ADDLs的单克隆抗体阻断了它们与突触结合位点的附着，并防止了tau蛋白的过度磷酸化。tau蛋白磷酸化被Src家族酪氨酸激酶抑制剂4-氨基-5-（4-氯苯基）-7-（叔丁基）吡唑并[3,4-d]嘧啶（PP1）以及磷脂酰肌醇-3-激酶抑制剂LY294002所阻断。值得注意的是，来自AD脑的含有Aβ寡聚体的可溶性水提取物也能诱导tau蛋白过度磷酸化，但非AD脑提取物则不能。Aβ寡聚体越来越多地被认为是AD中的主要神经毒素，目前的结果提供了一种统一机制，即寡聚体活性在AD病理学中直接与tau蛋白过度磷酸化相关联。
