Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
Department of Neurology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Acta Neuropathol Commun. 2018 Jan 3;6(1):1. doi: 10.1186/s40478-017-0501-1.
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 μm < 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.
阿尔茨海默病型神经原纤维缠结（NTs）和神经纤维缠结（NFTs）由 4 重复（4R）-tau、3 重复（3R）-tau 或两者的混合物组成。在海马体中，NFT 的数量以及 3R tau 的比例逐渐增加。如果这种 3R tau 的优先积累也发生在脑干中，它可能与阿尔茨海默病病理的进展有根本的关系。
对 23 例病例的中脑和脑桥脑干节段进行 4R 和 3R tau 的双重免疫荧光标记（Braak-NFT 阶段 I/II：8 例，III/IV：8 例，V/VI：7 例）。使用虚拟幻灯片系统，对高分辨率（0.645 μm/pixel）、聚焦良好的快照进行平铺，以覆盖整个脑节段。根据大小（NT < 200 μm < NFT）和染色模式（3R/4R）对每个病变进行分类。此外，还在相邻切片中检查了淀粉样β（Aβ）沉积的定位和数量，以便与 tau 进行比较。
从大约 286 吉字节的图像文件中获得的数据集中包含 847763 个 NTs 和 7859 个 NFTs。随着 NFT 阶段的进展，中脑的 3R tau 阳性 NTs 和 NFTs 的比例以及脑桥的 3R tau 阳性 NTs 逐渐增加，而脑桥的 3R tau 阳性 NFTs 的比例在早期阶段已经升高。在 NFT 阶段 I/II 时没有 Aβ 沉积，而在后期阶段存在时，其分布区域与 tau 不同。这些观察结果表明，3R tau 的比例增加是独立于 Aβ 沉积的。
这是对人类脑干 NFTs 和 NTs 的首次定量分析。我们证明了脑干神经纤维缠结变化中 3R tau 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是共有的，因此这种增加可能是阿尔茨海默病发病机制的基础。
