Specific Targeting of Tau Oligomers in Htau Mice Prevents Cognitive Impairment and Tau Toxicity Following Injection with Brain-Derived Tau Oligomeric Seeds
Specific Targeting of Tau Oligomers in Htau Mice Prevents Cognitive Impairment and Tau Toxicity Following Injection with Brain-Derived Tau Oligomeric Seeds
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DOI：
10.3233/jad-132477
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发表时间：
2014-01-01
影响因子：
4
通讯作者：
Kayed, Rakez
中科院分区：
文献类型：
--
作者：
Castillo-Carranza, Diana L.;Gerson, Julia E.;Kayed, Rakez
神经退行性疾病是世界上最大的健康危机之一，随着预期寿命的增加，受影响的人数将继续增加。最常见的神经退行性疾病阿尔茨海默病是tau蛋白病，其特征在于存在聚集的tau蛋白，即以神经元缠结的形式。从历史上看，神经元缠结被认为是阿尔茨海默病中主要的tau种类;然而，我们和其他人已经表明，tau寡聚体可能是毒性最大的形式，也是导致病理学传播的种类。我们开发了一种新的抗tau寡聚体特异性小鼠单克隆抗体（TOMA），并研究了抗tau寡聚体被动免疫在预防Htau小鼠中tau病理毒性方面的潜力。我们在3个月大的野生型和Htau小鼠脑内注射纯脑衍生的tau寡聚体，并研究了与相同剂量的非特异性IgG相比，单次60 μ g TOMA注射的保护作用，发现TOMA在治疗后长达1个月内对tau寡聚体的积累和认知缺陷提供保护。此外，我们在3个月大的野生型和Htau小鼠脑内注射纯脑源性tau寡聚体，并每两周注射60 μ g TOMA或非特异性IgG治疗动物。我们发现，长期给予TOMA作为预防性治疗是有效的，可以抑制寡聚tau蛋白并保留记忆功能。这些结果支持寡聚tau在疾病进展中的关键作用，并验证tau寡聚体作为潜在的药物靶标。
Neurodegenerative disease is one of the greatest health crises in the world and as life expectancy rises, the number of people affected will continue to increase. The most common neurodegenerative disease, Alzheimer's disease, is a tauopathy, characterized by the presence of aggregated tau, namely in the form of neurofibrillary tangles. Historically, neurofibrillary tangles have been considered the main tau species of interest in Alzheimer's disease; however, we and others have shown that tau oligomers may be the most toxic form and the species responsible for the spread of pathology. We developed a novel anti-tau oligomer-specific mouse monoclonal antibody (TOMA) and investigated the potential of anti-tau oligomer passive immunization in preventing the toxicity of tau pathology in Htau mice. We injected pure brain-derived tau oligomers intracerebrally in 3-month-old wild-type and Htau mice and investigated the protective effects of a single 60 mu g TOMA injection when compared to the same dose of non-specific IgG and found that TOMA conferred protection against the accumulation of tau oligomers and cognitive deficits for up to 1 month after treatment. Additionally, we injected pure brain-derived tau oligomers intracerebrally in 3-month-old wild-type and Htau mice and treated animals with biweekly injections of 60 mu g TOMA or non-specific IgG. We found that long-term administration of TOMA was effective as a preventative therapy, inhibiting oligomeric tau and preserving memory function. These results support the critical role of oligomeric tau in disease progression and validate tau oligomers as a potential drug target.