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

IF 21.2 1区 医学 Q1 NEUROSCIENCES Nature neuroscience Pub Date : 2024-12-24 DOI:10.1038/s41593-024-01829-7
Naoto Watamura, Martha S. Foiani, Sumi Bez, Mathieu Bourdenx, Alessia Santambrogio, Claire Frodsham, Elena Camporesi, Gunnar Brinkmalm, Henrik Zetterberg, Saisha Patel, Naoko Kamano, Mika Takahashi, Javier Rueda-Carrasco, Loukia Katsouri, Stephanie Fowler, Emir Turkes, Shoko Hashimoto, Hiroki Sasaguri, Takashi Saito, AFM Saiful Islam, Seico Benner, Toshihiro Endo, Katsuji Kobayashi, Chiho Ishida, Michele Vendruscolo, Masahito Yamada, Karen E. Duff, Takaomi C. Saido
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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.

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Nature neuroscience
Nature neuroscience 医学-神经科学
CiteScore
38.60
自引率
1.20%
发文量
212
审稿时长
1 months
期刊介绍: Nature Neuroscience, a multidisciplinary journal, publishes papers of the utmost quality and significance across all realms of neuroscience. The editors welcome contributions spanning molecular, cellular, systems, and cognitive neuroscience, along with psychophysics, computational modeling, and nervous system disorders. While no area is off-limits, studies offering fundamental insights into nervous system function receive priority. The journal offers high visibility to both readers and authors, fostering interdisciplinary communication and accessibility to a broad audience. It maintains high standards of copy editing and production, rigorous peer review, rapid publication, and operates independently from academic societies and other vested interests. In addition to primary research, Nature Neuroscience features news and views, reviews, editorials, commentaries, perspectives, book reviews, and correspondence, aiming to serve as the voice of the global neuroscience community.
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