Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration.
Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration.
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DOI：
10.1186/s13578-016-0124-4
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发表时间：
2016
影响因子：
7.5
通讯作者：
Lu KP
中科院分区：
文献类型：
--
作者：
Albayram O;Herbert MK;Kondo A;Tsai CY;Baxley S;Lian X;Hansen M;Zhou XZ;Lu KP
阿尔茨海默病（AD）脑的两个常见标志性病变之一是神经元缠结（NFT），其由过度磷酸化的tau蛋白（p-tau）组成。NFT也是其他神经退行性疾病的定义特征，并且最近已在患有慢性创伤性脑病（CTE）的患者的脑中鉴定。然而，在创伤性脑损伤（TBI）中通常直到损伤后数月或数年才观察到NFT。这就提出了一个问题，即NFT是TBI后长期神经退行性变的原因还是结果。磷酸化tau蛋白的两种构象，顺式p-tau蛋白和反式p-tau蛋白，这是由肽基脯氨酰异构酶Pin 1调节，以前已经确定。通过产生能够区分p-tau的顺式和反式同种型（分别为顺式p-tau和反式p-tau）的多克隆和单克隆抗体（Ab）对，顺式p-tau被鉴定为tau病理学的前体和AD、TBI和CTE中神经变性的早期驱动因素。组织学研究显示，在人类轻度认知障碍（MCI）、AD和CTE大脑的早期阶段以及在运动和军事相关的TBI之后，出现了强顺式p-tau。值得注意的是，顺式p-tau在闭合性头部损伤后数小时内出现，并且早于其他已知的致病性p-tau构象，包括寡聚体、前神经元缠结和NFT。重要的是，顺式p-tau单克隆抗体治疗不仅消除了顺式p-tau诱导和tau病理，而且还恢复了TBI小鼠模型中的许多神经病理和功能结果。因此，顺式p-tau是TBI和CTE中tau病理学的早期驱动因素，并且人体液中顺式p-tau的检测可能提供新的诊断和预后工具。此外，顺式p-tau抗体的人源化最终可被开发为AD、TBI和CTE的新治疗。
One of the two common hallmark lesions of Alzheimer’s disease (AD) brains is neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein (p-tau). NFTs are also a defining feature of other neurodegenerative disorders and have recently been identified in the brains of patients suffering from chronic traumatic encephalopathy (CTE). However, NFTs are not normally observed in traumatic brain injury (TBI) until months or years after injury. This raises the question of whether NFTs are a cause or a consequence of long-term neurodegeneration following TBI. Two conformations of phosphorylated tau, cis p-tau and trans p-tau, which are regulated by the peptidyl-prolyl isomerase Pin1, have been previously identified. By generating a polyclonal and monoclonal antibody (Ab) pair capable of distinguishing between cis and trans isoforms of p-tau (cis p-tau and trans p-tau, respectively), cis p-tau was identified as a precursor of tau pathology and an early driver of neurodegeneration in AD, TBI and CTE. Histological studies shows the appearance of robust cis p-tau in the early stages of human mild cognitive impairment (MCI), AD and CTE brains, as well as after sport- and military-related TBI. Notably, cis p-tau appears within hours after closed head injury and long before other known pathogenic p-tau conformations including oligomers, pre-fibrillary tangles and NFTs. Importantly, cis p-tau monoclonal antibody treatment not only eliminates cis p-tau induction and tau pathology, but also restores many neuropathological and functional outcome in TBI mouse models. Thus, cis p-tau is an early driver of tau pathology in TBI and CTE and detection of cis p-tau in human bodily fluids could potentially provide new diagnostic and prognostic tools. Furthermore, humanization of the cis p-tau antibody could ultimately be developed as a new treatment for AD, TBI and CTE.
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影响因子：
16
作者：
Lee TH;Chen CH;Suizu F;Huang P;Schiene-Fischer C;Daum S;Zhang YJ;Goate A;Chen RH;Zhou XZ;Lu KP
通讯作者：
Lu KP
影响因子：
5.3
作者：
Kandan, Nicholas M.;Pigino, Gustavo F.;Brady, Scott T.;Lazarov, Orly;Binder, Lester I.;Morfini, Gerardo A.
通讯作者：
Morfini, Gerardo A.
影响因子：
11.4
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
3.5
作者：
KHATOON, S;GRUNDKEIQBAL, I;IQBAL, K
通讯作者：
IQBAL, K
影响因子：
38.1
作者：
DeKosky, Steven T.;Blennow, Kaj;Ikonomovic, Milos D.;Gandy, Sam
通讯作者：
Gandy, Sam