Passive Immunization with Tau Oligomer Monoclonal Antibody Reverses Tauopathy Phenotypes without Affecting Hyperphosphorylated Neurofibrillary Tangles
Passive Immunization with Tau Oligomer Monoclonal Antibody Reverses Tauopathy Phenotypes without Affecting Hyperphosphorylated Neurofibrillary Tangles
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DOI：
10.1523/jneurosci.3192-13.2014
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发表时间：
2014-03-19
影响因子：
5.3
通讯作者：
Kayed, Rakez
中科院分区：
文献类型：
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作者：
Castillo-Carranza, Diana L.;Sengupta, Urmi;Kayed, Rakez
最近的研究结果表明，在神经元缠结（NFT）之前形成的tau寡聚体是神经退行性tau蛋白病（包括阿尔茨海默病（AD））中真正的神经毒性tau蛋白实体。在tau蛋白病动物模型中的研究表明，tau寡聚体在引发行为和认知障碍中起关键作用。在这里，我们使用了一种新的tau寡聚体特异性单克隆抗体（TOMA）的被动免疫小鼠表达突变的人tau蛋白。静脉内或脑室内给予单剂量TOMA足以逆转tau蛋白病小鼠模型中的运动和记忆缺陷60天，与tau寡聚体的快速减少一致，但不与磷酸化NFT或单体tau一致。我们的数据表明，抗体保护是由细胞外和快速外周清除介导的。这些发现提供了支持tau寡聚体在疾病进展中的关键作用的第一个直接证据，并验证了tau寡聚体作为治疗AD和其他神经退行性tau蛋白病的靶点。
Recent findings suggest that tau oligomers, which form before neurofibrillary tangles (NFTs), are the true neurotoxic tau entities in neurodegenerative tauopathies, including Alzheimer's disease (AD). Studies in animal models of tauopathy suggest that tau oligomers play a key role in eliciting behavioral and cognitive impairments. Here, we used a novel tau oligomer-specific monoclonal antibody (TOMA) for passive immunization in mice expressing mutant human tau. A single dose of TOMA administered either intravenously or intracerebroventricularly was sufficient to reverse both locomotor and memory deficits in a mouse model of tauopathy for 60 d, coincident with rapid reduction of tau oligomers but not phosphorylated NFTs or monomeric tau. Our data demonstrate that antibody protection is mediated by extracellular and rapid peripheral clearance. These findings provide the first direct evidence in support of a critical role for tau oligomers in disease progression and validate tau oligomers as a target for the treatment of AD and other neurodegenerative tauopathies.