Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer's disease
Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer's disease
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DOI：
10.1073/pnas.0509386103
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发表时间：
2006-02-07
影响因子：
11.1
通讯作者：
McGeer, PL
中科院分区：
文献类型：
--
作者：
Guo, JP;Arai, T;McGeer, PL
迄今为止，没有合理的解释，为什么斑块和缠结同时积累在阿尔茨海默病（AD）。我们通过Western印迹和ELISA证明了tau蛋白和淀粉样β蛋白（A β）之间可以形成稳定的复合物。该复合物增强了GSK 3 β对tau的磷酸化，但磷酸化随后促进复合物的解离。我们已经本地化的网站，这种相互作用，通过使用肽膜阵列。A β结合多种tau肽，特别是外显子7和9中的那些。这种结合通过特定丝氨酸和苏氨酸残基的磷酸化而急剧减少或消除。相反，tau在A β的中部至C末端区域结合多个A β肽。这种结合也被tau的GSK 313磷酸化显著降低。我们使用表面等离子体共振来确定A β对tau的结合亲和力，发现它在低纳摩尔范围内，几乎比tau本身高1,000倍。在AD和对照脑组织的可溶性提取物中，我们在ELISA中检测到与tau结合的A β。我们还通过AD脑组织的双重免疫染色发现，磷酸化的tau和A β在相同的神经元及其过程中形成单独的不溶性复合物。我们假设在AD中，发病机制的初始步骤可能是可溶性A β与可溶性非磷酸化tau的细胞内结合，从而促进tau磷酸化和A β成核。阻断A β最初与tau结合的位点可能会阻止AD中斑块和缠结的同时形成。
To date, there is no reasonable explanation as to why plaques and tangles simultaneously accumulate in Alzheimer's disease (AD). We demonstrate here by Western blotting and ELISA that a stable complex can form between tau and amyloid-beta protein (A beta). This complex enhances tau phosphorylation by GSK3 beta, but the phosphorylation then promotes dissociation of the complex. We have localized the sites of this interaction by using peptide membrane arrays. A beta binds to multiple tau peptides, especially those in exons 7 and 9. This binding is sharply reduced or abolished by phosphorylation of specific serine and threonine residues. Conversely, tau binds to multiple A beta peptides in the mid to C-terminal regions of A beta. This binding is also significantly decreased by GSK313 phosphorylation of tau. We used surface plasmon resonance to determine the binding affinity of A beta for tau and found it to be in the low nanomolar range and almost 1,000-fold higher than tau for itself. In soluble extracts from AD and control brain tissue, we detected A beta bound to tau in ELISAs. We also found by double immuno-staining of AD brain tissue that phosphorylated tau and A beta form separate insoluble complexes within the same neurons and their processes. We hypothesize that in AD, an initial step in the pathogenesis may be the intracellular binding of soluble A beta to soluble nonphosphorylated tau, thus promoting tau phosphorylation and A beta nucleation. Blocking the sites where A beta initially binds to tau might arrest the simultaneous formation of plaques and tangles in AD.