Department of Physics and Astronomy, Uppsala University, Box 516, SE-751 20 Uppsala, Sweden.
Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 141 84, Stockholm, Sweden.
ACS Chem Neurosci. 2021 Sep 15;12(18):3487-3496. doi: 10.1021/acschemneuro.1c00536. Epub 2021 Aug 31.
Alzheimer's disease and primary tauopathies are characterized by the presence of tau pathology in brain. Several tau positron emission tomography (PET) tracers have been developed and studied in Alzheimer's disease (AD), but there is still a lack of 4R-tau specific tracers for non-AD tauopathies. We here present the first computational study on the binding profiles of four tau different PET tracers, PI2620, CBD2115, PM-PBB3, and MK6240, to corticobasal degeneration (CBD) tau. The results showed different preferences for the various binding sites on the 4R fibril, and especially an entry site, a concave site, and a core site showed high binding affinity to these tracers. The core site and entry site both showed higher binding affinity than the surface sites, but the tracers were less likely to enter these sites. PI2620, CBD2115, and PM-PBB3 all showed higher binding affinities to CBD tau than the 3R/4R tracer MK6240. The same strategy has also been applied to AD tau fibrils, and significant differences in selectivity of binding sites were also observed. A higher binding affinity was observed for CBD2115 and PM-PBB3 to AD tau compared to PI2620. None of the studied tracers showed a selectivity for 4R compared to 3R/4R tau. This study clearly shows that identified binding sites from cryo-EM with low resolution can be further refined by metadynamics simulations in order to provide atomic resolution of the binding modes as well as of the thermodynamic properties.
阿尔茨海默病和原发性 tau 病的特征是脑内存在 tau 病理学。已经开发并研究了几种 tau 正电子发射断层扫描 (PET) 示踪剂用于阿尔茨海默病 (AD)，但对于非 AD tau 病仍然缺乏 4R-tau 特异性示踪剂。我们在此首次对四种 tau 不同 PET 示踪剂，即 PI2620、CBD2115、PM-PBB3 和 MK6240，与皮质基底节变性 (CBD) tau 的结合特性进行了计算研究。结果显示，这四种示踪剂对 4R 纤维上的不同结合部位具有不同的偏好性，特别是入口部位、凹面部位和核心部位对这些示踪剂具有高结合亲和力。核心部位和入口部位都比表面部位具有更高的结合亲和力，但示踪剂进入这些部位的可能性较小。PI2620、CBD2115 和 PM-PBB3 对 CBD tau 的结合亲和力均高于 3R/4R 示踪剂 MK6240。同样的策略也应用于 AD tau 纤维，并且观察到结合部位的选择性也有显著差异。与 PI2620 相比，CBD2115 和 PM-PBB3 对 AD tau 的结合亲和力更高。在所研究的示踪剂中，没有一种对 4R 表现出选择性，而对 3R/4R tau 则没有。本研究清楚地表明，通过低温电子显微镜获得的低分辨率结合部位可以通过元动力学模拟进一步细化，以便提供结合模式的原子分辨率以及热力学性质。
