Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, Alabama 35401, United States.
J Phys Chem Lett. 2021 Nov 18;12(45):11035-11041. doi: 10.1021/acs.jpclett.1c02660. Epub 2021 Nov 8.
Aggregation of the tau protein plays a central role in several neurodegenerative diseases collectively known as tauopathies, including Alzheimer's and Parkinson's disease. Tau misfolds into fibrillar β sheet structures that constitute the paired helical filaments found in neurofibrillary tangles. It is known that there can be significant structural heterogeneities in tau aggregates associated with different diseases. However, while structures of mature fibrils have been studied, the structural distributions in early-stage tau aggregates is not well-understood. In the present study, we use atomic force microscopy-IR to investigate nanoscale spectra of individual tau fibrils at different stages of aggregation and demonstrate the presence of multiple fibrillar polymorphs that exhibit different secondary structures. We further show that mature fibrils contain significant amounts of antiparallel β sheets. Our results are the very first application of nanoscale infrared spectroscopy to tau aggregates and underscore the promise of spatially resolved infrared spectroscopy for investigating protein aggregation.
tau 蛋白的聚集在几种神经退行性疾病中起着核心作用，这些疾病统称为 tau 病，包括阿尔茨海默病和帕金森病。tau 错误折叠成纤维状 β 片层结构，构成神经原纤维缠结中发现的双螺旋丝。已知与不同疾病相关的 tau 聚集物可能存在显著的结构异质性。然而，尽管已经研究了成熟原纤维的结构，但早期 tau 聚集物的结构分布还不是很清楚。在本研究中，我们使用原子力显微镜-红外光谱法（atomic force microscopy-IR）研究了不同聚集阶段的单个 tau 原纤维的纳米级光谱，并证明了存在多种表现出不同二级结构的纤维状多态性。我们进一步表明，成熟原纤维含有大量的反平行 β 片层。我们的结果是首次将纳米红外光谱法应用于 tau 聚集物，并强调了空间分辨红外光谱法在研究蛋白质聚集中的应用前景。
