Tau-Targeted Immunization Impedes Progression of Neurofibrillary Histopathology in Aged P301L Tau Transgenic Mice
Tau-Targeted Immunization Impedes Progression of Neurofibrillary Histopathology in Aged P301L Tau Transgenic Mice
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DOI：
10.1371/journal.pone.0026860
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发表时间：
2011-12-08
期刊：
影响因子：
3.7
通讯作者：
Ittner, Lars M.
中科院分区：
文献类型：
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作者：
Bi, Mian;Ittner, Arne;Ittner, Lars M.
在阿尔茨海默病（AD）大脑中，微管相关蛋白tau和淀粉样蛋白β (A β)分别以细胞内神经原纤维缠结（nft）和细胞外斑块的形式沉积。此外，在相当数量的额颞叶痴呆病例中也发现了Tau沉积。这些疾病的特点是进行性神经变性、智力丧失和行为改变。不幸的是，目前可用的治疗方法仅限于症状缓解。虽然针对A β的主动免疫在各种AD小鼠模型和AD患者中都显示出有效性，但针对致病性tau的免疫直到最近才被证明可以预防年轻tau转基因小鼠的病理。然而，如果转化为人类，诊断和治疗将在症状明显时常规进行，这意味着组织病理学变化已经进展。因此，我们在4、8和18月龄的P301L tau转基因pR5小鼠中使用主动免疫来靶向致病tau，这些小鼠在6月龄时出现NFT病理。在所有年龄组中，与对照pR5小鼠相比，治疗组的NFT病理显著减少。同样，病理部位的tau磷酸化也减少了。此外，年龄最大的治疗组星形细胞增多。综上所述，我们的数据表明，tau靶向免疫可以减缓小鼠NFT病理的进展，这对人类患者具有实际意义。
In Alzheimer's disease (AD) brains, the microtubule-associated protein tau and amyloid-beta (A beta) deposit as intracellular neurofibrillary tangles (NFTs) and extracellular plaques, respectively. Tau deposits are furthermore found in a significant number of frontotemporal dementia cases. These diseases are characterized by progressive neurodegeneration, the loss of intellectual capabilities and behavioral changes. Unfortunately, the currently available therapies are limited to symptomatic relief. While active immunization against A beta has shown efficacy in both various AD mouse models and patients with AD, immunization against pathogenic tau has only recently been shown to prevent pathology in young tau transgenic mice. However, if translated to humans, diagnosis and treatment would be routinely done when symptoms are overt, meaning that the histopathological changes have already progressed. Therefore, we used active immunization to target pathogenic tau in 4, 8, and 18 months-old P301L tau transgenic pR5 mice that have an onset of NFT pathology at 6 months of age. In all age groups, NFT pathology was significantly reduced in treated compared to control pR5 mice. Similarly, phosphorylation of tau at pathological sites was reduced. In addition, increased astrocytosis was found in the oldest treated group. Taken together, our data suggests that tau-targeted immunization slows the progression of NFT pathology in mice, with practical implications for human patients.