Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, 66045, United States.
Biochemistry. 2022 Jul 5;61(13):1243-1259. doi: 10.1021/acs.biochem.2c00111. Epub 2022 Jun 22.
Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) affect 6 million Americans, and they are projected to have an estimated health care cost of $355 billion for 2021. A histopathological hallmark of AD and many ADRDs is the aberrant intracellular accumulation of the microtubule-associated protein tau. These neurodegenerative disorders that contain tau aggregates are collectively known as tauopathies, and recent structural studies have shown that different tauopathies are characterized by different "strains" of tau filaments. In addition, mutations in the gene that encodes for tau protein expression have been associated with a group of tauopathies known as frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17 or familial frontotemporal dementia). studies often use small molecules to induce tau aggregation as tau is extremely soluble and does not spontaneously aggregate under typical laboratory conditions, and the use of authentic filaments to conduct studies is not feasible. This study highlights how different inducer molecules can have fundamental disparities to how disease-related mutations affect the aggregation dynamics of tau. Using three different classes of tau aggregation inducer molecules, we characterized disease-relevant mutations in tau's PGGG motifs at positions P301S, P332S, and P364S. When comparing these mutations to wild-type tau, we found that depending on the type of inducer molecule used, we saw fundamental differences in total aggregation, aggregation kinetics, immunoreactivity, and filament numbers, length, and width. These data are consistent with the possibility that different tau aggregation inducer molecules make different structural polymorphs, although this possibility would need to be confirmed by high-resolution techniques such as cryo-electron microscopy. The data also show that disease-associated missense mutations in tau impact tau aggregation differently depending on the mechanism of aggregation induction.
阿尔茨海默病（AD）和与阿尔茨海默病相关的痴呆症（ADRD）影响了 600 万美国人，预计 2021 年的医疗保健费用将达到 3550 亿美元。AD 和许多 ADRD 的组织病理学标志是微管相关蛋白 tau 的异常细胞内积累。这些包含 tau 聚集物的神经退行性疾病统称为 tau 病，最近的结构研究表明，不同的 tau 病具有不同的“株系”tau 纤维。此外，编码 tau 蛋白表达的基因突变与一组 tau 病有关，这些 tau 病称为与染色体 17 相关的额颞叶痴呆伴帕金森病（FTDP-17 或家族性额颞叶痴呆）。研究通常使用小分子诱导 tau 聚集，因为 tau 非常可溶，在典型的实验室条件下不会自发聚集，并且使用真实纤维进行研究是不可行的。这项研究强调了不同的诱导分子如何对疾病相关突变如何影响 tau 的聚集动力学产生根本差异。使用三种不同类别的 tau 聚集诱导分子，我们在 tau 的 PGGG 基序中位于 P301S、P332S 和 P364S 的位置表征了疾病相关突变。将这些突变与野生型 tau 进行比较时，我们发现，取决于所使用的诱导分子类型，我们在总聚集、聚集动力学、免疫反应性以及纤维数量、长度和宽度方面看到了根本差异。这些数据与不同的 tau 聚集诱导分子形成不同结构多晶型的可能性一致，尽管这一可能性需要通过低温电子显微镜等高分辨率技术来证实。数据还表明，tau 中的疾病相关错义突变会根据聚集诱导机制的不同而对 tau 聚集产生不同的影响。
