MICROTUBULE-ASSOCIATED PROTEIN TAU (TAU) IS A MAJOR ANTIGENIC COMPONENT OF PAIRED HELICAL FILAMENTS IN ALZHEIMER-DISEASE
MICROTUBULE-ASSOCIATED PROTEIN TAU (TAU) IS A MAJOR ANTIGENIC COMPONENT OF PAIRED HELICAL FILAMENTS IN ALZHEIMER-DISEASE
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DOI：
10.1073/pnas.83.11.4044
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发表时间：
1986-06-01
影响因子：
11.1
通讯作者：
SELKOE, DJ
中科院分区：
文献类型：
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作者：
KOSIK, KS;JOACHIM, CL;SELKOE, DJ
在衰老和阿尔茨海默病中积聚在人类神经元内的成对螺旋丝（PHF）的详细蛋白质组成尚不清楚。然而，通过免疫细胞化学技术已经推测出某些成分的特性。尽管PHF与神经丝蛋白和微管相关蛋白（MAP）2具有共同的表位，但我们报道有证据表明MAP tau（τ）似乎是它们的主要抗原成分。用十二烷基硫酸钠（NaDodSO₄）提取的、部分纯化的PHF（不含正常的细胞骨架成分，包括τ）免疫兔子，始终会产生针对τ的抗体，但不会产生例如针对神经丝的抗体。这种PHF抗体可标记来自大鼠和人类大脑的所有不同的胎儿期和成熟期的τ形式。用热稳定的MAP（富含τ）吸附PHF抗血清会导致人脑切片中神经原纤维缠结（NFT）的染色几乎完全消失。一种亲和纯化的针对τ的抗体可特异性标记人脑切片中的NFT和老年斑的神经突以及十二烷基硫酸钠提取的NFT。τ免疫反应性NFT经常延伸到锥体神经元的顶树突中，这表明这种轴突蛋白在细胞内的定位异常。τ和PHF抗体在电泳转移印迹上对τ蛋白的标记相同，并对代表十二烷基硫酸钠不溶性PHF的凝胶排阻蛋白进行染色，该蛋白存在于人脑匀浆中。在阿尔茨海默病中神经元内改变的τ蛋白的逐渐积累可能导致微管不稳定，从而导致分子和细胞器的有效运输丧失，并最终导致神经元死亡。
The detailed protein composition of the paired helical filaments (PHF) that accumulate in human neurons in aging and Alzheimer disease is unknown. However, the identity of certain components has been surmised by using immunocytochemical techniques. Whereas PHF share epitopes with neurofilament proteins and microtubule-associated protein (MAP) 2, we report evidence that the MAP tau (.tau.) appears to be their major antigenic component. Immunization of rabbits with NaDodSO4-extracted, partially purified PHF (free of normal cytoskeletal elements, including .tau.) consistently produces antibodies to .tau. but not, for examle, to neurofilaments. Such PHF antibodies label all of the heterogeneous fetal and mature forms of .tau. from rat and human brain. Adsorption of PHF antisera with heat-stable MAPs (rich in .tau.) results in almost complete loss of staining of neurofibrillary tangles (NFT) in human brain sections. An affinity-purified antibody to .tau. specifically labels NFT and the neurites of senile plaques in human brain sections as well as NaDodSO4-extracted NFT. .tau.-Immunoreactive NFT frequently extend into the apical dendrites of pyramidal neurons, suggesting an aberrant intracellular locus for this axonal protein. .tau. and PHF antibodies label .tau. proteins identically on electrophoretic transfer blots and stain the gel-excluded protein representing NaDodSO4-insoluble PHF in homogenates of human brain. The progressive accumulation of altered .tau. protein in neurons in Alzheimer disease may result in instability of microtubules, consequent loss of effective transport of molecules and organelles, and, ultimately, neuronal death.