日本理化学研究所脑神经科学研究中心Takaomi C. Saido等研究人员合作发现，体内tau蛋白的过度磷酸化与突触丧失和行为异常相关并不依赖于tau种子。2024年12月24日，《自然—神经科学》杂志在线发表了这项成果。

研究人员开发了一系列靶向小鼠，这些小鼠在人源化的MAPT基因中表达导致额颞叶痴呆的突变，用于研究tau病理的早期阶段。MAPT^Int10+3G>A和MAPT^{S305N;Int10+3G>A}小鼠在海马和内嗅皮层中显示出丰富的过度磷酸化tau，但它们并未形成具有种子活性的纤维结构。过度磷酸化tau的积累伴随着神经突起退化、可存活突触的丧失以及行为异常的指示。

这些结果表明，即使没有纤维状的高阶结构，神经毒性仍然可以发生，且tau过度磷酸化可能参与tau病理中最早的病因学事件，特别是在显示亚型比例失衡的tau病中。

据悉，tau病理是多种神经退行性疾病的特征，包括额颞叶痴呆和阿尔茨海默病。然而，tau的毒性形式以及事件的发生顺序仍不清楚，主要是由于缺乏能够测试假设的tau病理起始和进展的生理学模型。

附：英文原文

Title: In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds

Author: Watamura, Naoto, Foiani, Martha S., Bez, Sumi, Bourdenx, Mathieu, Santambrogio, Alessia, Frodsham, Claire, Camporesi, Elena, Brinkmalm, Gunnar, Zetterberg, Henrik, Patel, Saisha, Kamano, Naoko, Takahashi, Mika, Rueda-Carrasco, Javier, Katsouri, Loukia, Fowler, Stephanie, Turkes, Emir, Hashimoto, Shoko, Sasaguri, Hiroki, Saito, Takashi, Islam, AFM Saiful, Benner, Seico, Endo, Toshihiro, Kobayashi, Katsuji, Ishida, Chiho, Vendruscolo, Michele, Yamada, Masahito, Duff, Karen E., Saido, Takaomi C.

Issue&Volume: 2024-12-24

Abstract: Tau pathology is a hallmark of several neurodegenerative diseases, including frontotemporal dementia and Alzheimer’s disease. However, the sequence of events and the form of tau that confers toxicity are still unclear, due in large part to the lack of physiological models of tauopathy initiation and progression in which to test hypotheses. We have developed a series of targeted mice expressing frontotemporal-dementia-causing mutations in the humanized MAPT gene to investigate the earliest stages of tauopathy. MAPTInt10+3G>A and MAPTS305N;Int10+3G>A lines show abundant hyperphosphorylated tau in the hippocampus and entorhinal cortex, but they do not develop seed-competent fibrillar structures. Accumulation of hyperphosphorylated tau was accompanied by neurite degeneration, loss of viable synapses and indicators of behavioral abnormalities. Our results demonstrate that neuronal toxicity can occur in the absence of fibrillar, higher-order structures and that tau hyperphosphorylation is probably involved in the earliest etiological events in tauopathies showing isoform ratio imbalance.

DOI: 10.1038/s41593-024-01829-7

Source: https://www.nature.com/articles/s41593-024-01829-7