Cryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir.
Cryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir.
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DOI：
10.1016/j.jmb.2023.168025
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发表时间：
2023-06-01
影响因子：
5.6
通讯作者：
Scheres SHW
中科院分区：
文献类型：
--
作者：
Shi Y;Ghetti B;Goedert M;Scheres SHW
正电子发射断层扫描（PET）成像可以监测淀粉样蛋白聚集在活脑中的进展。[18F]-Flortaucipir是唯一获批用于tau聚集可视化的PET示踪剂化合物。在这里，我们描述了在存在和不存在flortaucipir的情况下对tau丝的冷冻EM实验。我们使用了从患有阿尔茨海默病（AD）的个体的脑和从患有原发性年龄相关性tau蛋白病（PART）与慢性创伤性脑病（CTE）的共同病理学的个体的脑中分离的tau丝。出乎意料的是，我们无法观察到AD成对螺旋或直丝（PHF或SF）的flortaucipir的额外cryo-EM密度，但我们确实观察到PART病例中flortaucipir与CTE I型丝结合的密度。在后者中，flortaucipir以1：1的分子化学计量与tau结合，邻近赖氨酸353和天冬氨酸358。通过采用相对于螺旋轴倾斜的几何形状，相邻tau单体之间的4.7 μ m距离与相邻flortaucipir分子之间的π-π-堆叠一致的3.5 μ m距离一致。
Positron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [18F]-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.
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影响因子：
7.1
作者：
Lowe VJ;Curran G;Fang P;Liesinger AM;Josephs KA;Parisi JE;Kantarci K;Boeve BF;Pandey MK;Bruinsma T;Knopman DS;Jones DT;Petrucelli L;Cook CN;Graff-Radford NR;Dickson DW;Petersen RC;Jack CR Jr;Murray ME
通讯作者：
Murray ME
影响因子：
29
作者：
Leuzy, Antoine;Smith, Ruben;Hansson, Oskar
通讯作者：
Hansson, Oskar
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
4.2
作者：
Lesman-Segev, Orit H.;La Joie, Renaud;Rabinovici, Gil D.
通讯作者：
Rabinovici, Gil D.