Tau oligomers and tau toxicity in neurodegenerative disease.
Tau oligomers and tau toxicity in neurodegenerative disease.
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DOI：
10.1042/bst20120134
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发表时间：
2012-08
影响因子：
3.9
通讯作者：
Binder LI
中科院分区：
文献类型：
--
作者：
Ward SM;Himmelstein DS;Lancia JK;Binder LI
AD（阿尔茨海默氏病）是一种进行性神经退行性疾病，其特征是细胞外β-淀粉样肽积累和细胞内tau蛋白积累。尽管有大量证据表明 tau 蛋白与神经退行性疾病有关，但 tau 蛋白介导的神经毒性的确切机制仍然难以捉摸。据报道，AD 脑组织中存在缺乏神经原纤维缠结的 tau 阳性前缠结神经元。为了研究这种非纤维状 tau，我们制备了一种新型单克隆抗体，命名为 TOC1（tau 寡聚复合物 1），它选择性标记 tau 二聚体和寡聚体，但不标记丝状体。时程分析和抗体标记表明寡聚物是 AD 发病机制中的早期事件。使用鱿鱼轴浆测定，我们证明聚集的 tau 蛋白会抑制顺行 FAT（快速轴突运输），而单体 tau 蛋白则没有效果。这种抑制需要一小段 N 端氨基酸，称为 PAD（磷酸酶激活结构域）。使用 PAD 特异性抗体 TNT1（tau N 末端 1），我们证明患病神经元中 PAD 暴露增加，这导致 FAT 抑制增加。抗体与早期 AD 标记 AT8 共标记表明，与 TOC1 类似，TNT1 表达代表 AD 发病机制的早期事件。最后，还在鱿鱼轴浆测定中研究了分子伴侣 Hsp70（热休克蛋白 70）的影响。我们证明，Hsp70 优先与 tau 寡聚体结合而不是细丝结合，并防止两种形式聚集 tau 的混合物观察到的顺行 FAT 抑制。总之，这些发现支持了这样的假设：tau 寡聚物是神经退行性疾病中 tau 的有毒形式。
AD (Alzheimer's disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid β-peptide and the intracellular accumulation of tau. Although there is much evidence linking tau to neurodegeneration, the precise mechanism of tau-mediated neurotoxicity remains elusive. The presence of tau-positive pre-tangle neurons lacking neurofibrillary tangles has been reported in AD brain tissue. In order to study this non-fibrillar tau, we generated a novel monoclonal antibody, named TOC1 (tau oligomeric complex 1), which selectively labels tau dimers and oligomers, but does not label filaments. Time-course analysis and antibody labelling indicates that oligomers appear as an early event in AD pathogenesis. Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect. This inhibition requires a small stretch of N-terminal amino acids termed the PAD (phosphatase-activation domain). Using a PAD-specific antibody, TNT1 (tau N-terminal 1), we demonstrate that PAD exposure is increased in diseased neurons and this leads to an increase in FAT inhibition. Antibody co-labelling with the early-AD marker AT8 indicates that, similar to TOC1, TNT1 expression represents an early event in AD pathogenesis. Finally, the effects of the molecular chaperone Hsp70 (heat-shock protein 70) were also investigated within the squid axoplasm assay. We illustrate that Hsp70 preferentially binds to tau oligomers over filaments and prevents anterograde FAT inhibition observed with a mixture of both forms of aggregated tau. Together, these findings support the hypothesis that tau oligomers are the toxic form of tau in neurodegenerative disease.