Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: https://twitter.com/GhettiBernardi1.
J Mol Biol. 2023 Jun 1;435(11):168025. doi: 10.1016/j.jmb.2023.168025. Epub 2023 Jun 16.
Positron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [F]-Flortaucipir is the only approved PET tracer compound for the visualisation of tau aggregation. Here, we describe cryo-EM experiments on tau filaments in the presence and absence of flortaucipir. We used tau filaments isolated from the brain of an individual with Alzheimer's disease (AD), and from the brain of an individual with primary age-related tauopathy (PART) with a co-pathology of chronic traumatic encephalopathy (CTE). Unexpectedly, we were unable to visualise additional cryo-EM density for flortaucipir for AD paired helical or straight filaments (PHFs or SFs), but we did observe density for flortaucipir binding to CTE Type I filaments from the case with PART. In the latter, flortaucipir binds in a 1:1 molecular stoichiometry with tau, adjacent to lysine 353 and aspartate 358. By adopting a tilted geometry with respect to the helical axis, the 4.7 Å distance between neighbouring tau monomers is reconciled with the 3.5 Å distance consistent with π-π-stacking between neighbouring molecules of flortaucipir.
正电子发射断层扫描（PET）成像可用于监测活体大脑中淀粉样蛋白聚集的进展。[F]-氟替卡滨是唯一被批准用于可视化 tau 聚集的 PET 示踪化合物。在这里，我们描述了在存在和不存在氟替卡滨的情况下 tau 纤维的冷冻电镜实验。我们使用了从阿尔茨海默病（AD）患者大脑中分离出的 tau 纤维，以及从原发性年龄相关性 tau 病（PART）患者大脑中分离出的 tau 纤维，该患者具有慢性创伤性脑病（CTE）的共病。出乎意料的是，我们无法为 AD 配对螺旋或直丝（PHF 或 SF）的氟替卡滨可视化额外的冷冻电镜密度，但我们确实观察到了来自 PART 病例的 CTE 型 I 丝上的氟替卡滨结合密度。在后一种情况下，氟替卡滨与 tau 以 1:1 的分子化学计量比结合，位于赖氨酸 353 和天冬氨酸 358 附近。通过相对于螺旋轴采用倾斜的几何形状，相邻 tau 单体之间 4.7Å 的距离与 3.5Å 的距离一致，这与相邻氟替卡滨分子之间的π-π 堆积一致。
