Extracellular Tau Levels Are Influenced by Variability in Tau That Is Associated with Tauopathies
Extracellular Tau Levels Are Influenced by Variability in Tau That Is Associated with Tauopathies
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DOI：
10.1074/jbc.m112.380642
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发表时间：
2012-12-14
影响因子：
4.8
通讯作者：
Goate, Alison M.
中科院分区：
文献类型：
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作者：
Karch, Celeste M.;Jeng, Amanda T.;Goate, Alison M.
Tau病是一类以过度磷酸化的Tau的细胞内聚集体为标志的神经变性疾病。这些疾病可能通过散发性机制发生，其中遗传变异代表疾病的风险因素，如阿尔茨海默病（AD）的情况。在AD中，与对照相比，病例中可溶性Tau/pTau-181的脑脊液（CSF）水平更高。额颞叶痴呆（FTD）病例的一个子集通过家族机制发生，其中编码Tau的基因MAPT突变是显性遗传的。在表达MAPT突变的症状性FTD患者中，CSF Tau水平略微升高，但显著低于AD患者。我们试图通过测量培养细胞中的细胞外Tau来模拟CSF Tau变化。全长单体细胞外总Tau和pTau-181在表达内源性Tau的人神经母细胞瘤细胞中、在过表达野生型Tau的人非神经元细胞中和在小鼠皮质神经元中是可检测的。Tau同种型影响Tau释放的速率，由此N末端（外显子2/3）和微管结合重复序列长度有助于Tau从细胞释放。与过表达野生型Tau的细胞相比，过表达FTD相关MAPT突变的细胞产生显著更少的细胞外总Tau，而不改变细胞内总Tau水平。这项研究表明，在没有疾病或毒性的情况下，细胞主动释放Tau，并且Tau释放通过与Tau蛋白病相关的Tau蛋白的变化而改变。
Tauopathies are a class of neurodegenerative diseases marked by intracellular aggregates of hyperphosphorylated Tau. These diseases may occur by sporadic mechanisms in which genetic variants represent risk factors for disease, as is the case in Alzheimer disease (AD). In AD, cerebrospinal fluid (CSF) levels of soluble Tau/pTau-181 are higher in cases compared with controls. A subset of frontotemporal dementia (FTD) cases occur by a familial mechanism in which MAPT, the gene that encodes Tau, mutations are dominantly inherited. In symptomatic FTD patients expressing a MAPT mutation, CSF Tau levels are slightly elevated but are significantly lower than in AD patients. We sought to model CSF Tau changes by measuring extracellular Tau in cultured cells. Full-length, monomeric extracellular total Tau and pTau-181 were detectable in human neuroblastoma cells expressing endogenous Tau, in human non-neuronal cells overexpressing wild-type Tau, and in mouse cortical neurons. Tau isoforms influence the rate of Tau release, whereby the N terminus (exons 2/3) and microtubule binding repeat length contribute to Tau release from the cell. Compared with cells overexpressing wild-type Tau, cells overexpressing FTD-associated MAPT mutations produce significantly less extracellular total Tau without altering intracellular total Tau levels. This study demonstrates that cells actively release Tau in the absence of disease or toxicity, and Tau release is modified by changes in the Tau protein that are associated with tauopathies.