Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau₄₅₋₂₃₀ transgenic mice.
Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau₄₅₋₂₃₀ transgenic mice.
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DOI：
10.1016/j.neuroscience.2014.06.017
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发表时间：
2014-09-05
期刊：
影响因子：
3.3
通讯作者：
Ferreira, A.
中科院分区：
文献类型：
--
作者：
Lang, A. E.;Methner, D. N. Riherd;Ferreira, A.
神经退行性疾病中 tau 病理学的补充机制尚未阐明。在这些机制中，异常的 tau 磷酸化受到了最多的关注，因为阿尔茨海默病 (AD) 和称为 tau 病的相关疾病中存在的神经原纤维缠结是由这种微管相关蛋白的过度磷酸化形式组成的。最近，我们发现钙蛋白酶介导的裂解导致 17 kDa tau45-230 片段的生成，是这些疾病中的保守机制。为了深入了解该片段在神经变性中的作用，我们培育了表达 tau45-230 的转基因小鼠并表征了它们的表型。我们的结果显示，与野生型对照相比，转基因 tau45-230 小鼠海马锥体细胞层的细胞死亡显着增加。此外，早在出生后六个月，转基因海马神经元中就检测到显着的突触丧失。这些突触变化伴随着 N-甲基-D-天冬氨酸谷氨酸 (NMDA) 受体亚基表达的变化。此外，使用莫里斯水迷宫和恐惧条件反射测试发现转基因小鼠的功能异常。这些结果表明，tau45-230 的积累至少部分地导致了 AD 和其他 tau 病中的神经元变性和一些行为变化。总的来说，这些数据提供了第一个直接证据，证明在这些疾病的背景下，在原位发育的脊椎动物神经元中生物产生的 tau 片段具有毒性作用。
The complement of mechanisms underlying tau pathology in neurodegenerative disorders has yet to be elucidated. Among these mechanisms, abnormal tau phosphorylation has received the most attention because neurofibrillary tangles present in Alzheimer’s disease (AD) and related disorders known as tauopathies are composed of hyperphosphorylated forms of this microtubule-associated protein. More recently, we showed that calpain-mediated cleavage leading to the generation of the 17 kDa tau45-230 fragment is a conserved mechanism in these diseases. To obtain insights into the role of this fragment in neurodegeneration, we generated transgenic mice that express tau45-230 and characterized their phenotype. Our results showed a significant increase in cell death in the hippocampal pyramidal cell layer of transgenic tau45-230 mice when compared to wild type controls. In addition, significant synapse loss was detected as early as six months after birth in transgenic hippocampal neurons. These synaptic changes were accompanied by alterations in the expression of the N-methyl-D-aspartate glutamate (NMDA) receptor subunits. Furthermore, functional abnormalities were detected in the transgenic mice using Morris Water Maze and fear conditioning tests. These results suggest that the accumulation of tau45-230 is responsible, at least in part, for neuronal degeneration and some behavioral changes in AD and other tauopathies. Collectively, these data provide the first direct evidence of the toxic effects of a tau fragment biologically produced in the context of these diseases in vertebrate neurons that develop in situ.
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DOI：
10.1016/0165-3806(89)90023-0
发表时间：
1989-10-01
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
--
作者：
FERREIRA, A;BUSCIGLIO, J;CACERES, A
通讯作者：
CACERES, A
影响因子：
64.8
作者：
CACERES, A;KOSIK, KS
通讯作者：
KOSIK, KS
影响因子：
16.2
作者：
BRAMBLETT, GT;GOEDERT, M;LEE, VMY
通讯作者：
LEE, VMY
DOI：
10.1073/pnas.76.1.514
发表时间：
1979-01-01
影响因子：
11.1
作者：
BOTTENSTEIN, JE;SATO, GH
通讯作者：
SATO, GH
影响因子：
2.9
作者：
BENSADOUN, A;WEINSTEIN, D
通讯作者：
WEINSTEIN, D