In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

在与 Tau 蛋白细胞内聚集相关的人类神经退行性疾病中，Tau 细丝的有序核心采用不同的折叠。在这里，我们分析了从受朊蛋白-蛋白脑淀粉样血管病 (PrP-CAA) 影响的个体大脑中分离的 Tau 细丝，其中PRNP基因中的无义突变导致 PrP 的翻译提前终止（Q160Ter 或 Q160X）和 Gerstmann –Sträussler-Scheinker (GSS) 病，PRNP基因中的错义突变导致 PrP 残基 198 (F198S) 处的氨基酸取代。与这两个PRNP突变相关的临床和神经病理学表型是不同的; 然而，对这两种遗传变异的神经病理学分析一致表明，神经元中存在大量由丝状 Tau 聚集体构成的神经原纤维缠结 (NFT)。我们报告 PrP-CAA (Q160X) 和 GSS (F198S) 中的 Tau 丝由 3 重复和 4 重复 Tau 亚型组成，与阿尔茨海默病 (AD) 中的 NFT 具有惊人的相似性。在 PrP-CAA (Q160X) 中，Tau 细丝由成对的螺旋细丝 (PHF) 和直​​细丝 (SF) 制成，而在 GSS (F198S) 中，仅发现 PHF。从 PrP-CAA (Q160X) 和 GSS (F198S) 大脑中提取的 Tau 细丝的质谱分析显示，翻译后修饰的存在与 AD 的 Tau 聚集体中所见的修饰相当。冷冻电镜分析表明，从 PrP-CAA (Q160X) 和 GSS (F198S) 获得的 Tau 丝的原子模型与 AD 的 Tau 丝的原子模型相同，因此与 Pick 病、慢性创伤性脑病的模型不同和皮质基底节变性。我们的数据支持这样的假设，即在存在细胞外淀粉样蛋白沉积物的情况下，无论淀粉样蛋白的一级氨基酸序列如何，相似的分子机制在相同 Tau 丝的形成中起作用。