Brainstem tau pathology in Alzheimer's disease is characterized by increase of three repeat tau and independent of amyloid β.
Brainstem tau pathology in Alzheimer's disease is characterized by increase of three repeat tau and independent of amyloid β.
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DOI：
10.1186/s40478-017-0501-1
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发表时间：
2018-01-03
影响因子：
7.1
通讯作者：
Uchihara T
中科院分区：
文献类型：
--
作者：
Uematsu M;Nakamura A;Ebashi M;Hirokawa K;Takahashi R;Uchihara T
阿尔茨海默型神经纤维缠结（NT）和神经纤维缠结（NFT）由4个重复（4 R）-tau、3个重复（3R）-tau或两者的混合物组成。在海马中，NFT的数量和3R tau的比例逐渐增加。如果3R tau的这种优先积累也发生在脑干中，则它可能与阿尔茨海默病病理学的进展基本相关。对23例（Braak-NFT分期I/II：8例，III/IV：8例，V/VI：7例）脑干的中脑和脑桥切片进行4 R和3R tau双重免疫荧光标记。使用虚拟载玻片系统平铺高分辨率（0.645 μm/像素）的对焦快照，以覆盖整个脑切片。根据大小（NT < 200 μm2 < NFT）和染色特征（3R/4 R）对每个病变进行分类。此外，在相邻切片中检查淀粉样蛋白β（Aβ）沉积物的定位和数量，以与tau蛋白进行比较。从大约286千兆字节的图像文件中获得的数据集包括847，763个NT和7859个NFT。随着NFT分期的进展，中脑3R tau蛋白阳性NT和NFT的比例以及脑桥3R tau蛋白阳性NT的比例逐渐增加，而脑桥3R tau蛋白阳性NFT的比例在早期已经升高。Aβ沉积在NFT I/II期不存在，当在后期出现时，其区域分布与tau不同。这些观察结果表明，3R tau比例的逐渐增加与Aβ沉积无关。这是第一次对人类脑干中的NFT和NT进行定量分析。我们证明，3 R tau在脑干神经原纤维变化中的比例随着疾病的进展而增加。由于这种现象在脑干和海马体之间共享，这种增加可能是阿尔茨海默病发病机制的基础。本文的在线版本（10.1186/s40478-017-0501-1）包含补充材料，可供授权用户使用。
Alzheimer-type neuropil threads (NTs) and neurofibrillary tangles (NFTs) are comprised of either 4 repeat (4R)-tau, 3 repeat (3R)-tau, or a mixture of both. In the hippocampus, the number of NFTs, and the proportion of 3R tau progressively increases. If this preferential accumulation of 3R tau also occurs in the brainstem, it may be fundamentally related to progression of Alzheimer pathology. Midbrain and pontine sections of brainstems from 23 cases (Braak-NFT stages I/II: 8, III/IV: 8, and V/VI: 7) were double immunofluorolabeled for 4R and 3R tau. High-resolution (0.645 μm/pixel), in-focus snapshots were tiled to cover entire brain sections using a virtual slide system. Each lesion was classified by size (NT < 200 μm2 < NFT) and staining profile (3R/4R). In addition, the localization and quantity of amyloid β (Aβ) deposits were examined in adjacent sections for comparison with tau. The data sets obtained from approximately 286 gigabytes of image files consisted of 847,763 NTs and 7859 NFTs. The proportion of 3R tau-positive NTs and NFTs in the midbrain, and 3R tau-positive NTs in the pons gradually increased with advancing NFT stages, while the proportion of 3R tau-positive NFTs in the pons was already elevated at early stages. Aβ deposits were absent at NFT stages I/II, and when present at later stages, their regional distribution was different from that of tau. These observations suggest that a progressive increase in the proportion of 3R tau occurs independently of Aβ deposits. This is the first quantitative analysis of NFTs and NTs in the human brainstem. We demonstrate that the proportion of 3R tau in the brainstem neurofibrillary changes increases with disease progression. Because this phenomenon is shared between the brainstem and the hippocampus, this increase may be fundamental to the pathogenesis of Alzheimer disease. The online version of this article (10.1186/s40478-017-0501-1) contains supplementary material, which is available to authorized users.
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