Seed-competent high-molecular-weight tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients
Seed-competent high-molecular-weight tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients
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DOI：
10.1002/ana.24716
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发表时间：
2016-09-01
影响因子：
11.2
通讯作者：
Hyman, Bradley T.
中科院分区：
文献类型：
--
作者：
Takeda, Shuko;Commins, Caitlin;Hyman, Bradley T.
脑脊液（CSF）tau蛋白是评估阿尔茨海默病（AD）患者神经病理学变化的一个很好的替代标志物。然而，AD CSF中升高的tau蛋白是否只是神经退行性变的标志物，或者实际上是疾病过程的一部分尚不确定。此外，还不知道CSF tau与最近描述的可溶性高分子量（HMW）物质如何相关，所述可溶性高分子量（HMW）物质在死后AD脑中发现并且可以被神经元和种子聚集体摄取。包括间质液（ISF）和CSF以及AD患者的死后脑室和生前腰椎CSF。AD小鼠模型可被细胞摄取并诱导细胞内聚集。来自AD患者的脑室CSF含有一种罕见的HMW tau物质，其具有更高的接种活性。值得注意的是，在AD患者的腰椎CSF中也检测到HMW tau种类，并且其水平与对照受试者相比显著升高。这些发现表明，来自AD脑的CSF含有潜在的生物活性HMW tau种类，为CSF tau的作用和AD生物标志物的开发提供了新的见解。《神经病学年鉴》2016;80：355-367
ObjectiveCerebrospinal fluid (CSF) tau is an excellent surrogate marker for assessing neuropathological changes that occur in Alzheimer's disease (AD) patients. However, whether the elevated tau in AD CSF is just a marker of neurodegeneration or, in fact, a part of the disease process is uncertain. Moreover, it is unknown how CSF tau relates to the recently described soluble high-molecular-weight (HMW) species that is found in the postmortem AD brain and can be taken up by neurons and seed aggregates.MethodsWe have examined seeding and uptake properties of brain extracellular tau from various sources, including interstitial fluid (ISF) and CSF from an AD transgenic mouse model and postmortem ventricular and antemortem lumbar CSF from AD patients.ResultsWe found that brain ISF and CSF tau from the AD mouse model can be taken up by cells and induce intracellular aggregates. Ventricular CSF from AD patients contained a rare HMW tau species that exerted a higher seeding activity. Notably, the HMW tau species was also detected in lumbar CSF from AD patients, and its levels were significantly elevated compared to control subjects. HMW tau derived from CSF of AD patients was seed competent in vitro.InterpretationThese findings suggest that CSF from an AD brain contains potentially bioactive HMW tau species, giving new insights into the role of CSF tau and biomarker development for AD. Ann Neurol 2016;80:355-367