冬眠中可逆的tau蛋白过度磷酸化:血液生物标志物和脑组织研究。

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY
Wagner S. Brum, Laia Montoliu-Gaya, Gunnar Brinkmalm, Diana Piotrowska, Elena Camporesi, Carsten Jäger, Helena S. Isaksson, Sven Martin, Jonas Kindberg, Juan Lantero-Rodriguez, João Pedro Ferrari-Souza, Alexis Moscoso, Andrea L. Benedet, Shorena Janelidze, Johan Gobom, Henrik Zetterberg, Oskar Hansson, Eduardo R. Zimmer, Nicholas J. Ashton, Thomas Arendt, Tammaryn Lashley, Jens T. Stieler, Max Holzer, Ole Fröbert, Kaj Blennow
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引用次数: 0

摘要

Tau过度磷酸化是阿尔茨海默病(AD)等Tau病变的一个关键神经病理特征,在哺乳动物冬眠期间也会发生生理反应,并在觉醒时完全逆转,这为研究Tau代谢提供了一个独特的翻译模型。然而,关于冬眠期间不溶性和可溶性tau蛋白的改变以及冬眠哺乳动物大脑中tau蛋白片段浓度模式的数据有限。我们使用临床验证的免疫测定和免疫沉淀质谱(IP-MS)技术,对10只自由放养的棕熊(Ursus arctos)的血浆样本中的tau生物标志物进行了定量分析,这些棕熊是在夏季活跃期和冬季冬眠期间捕获的。我们还分析了10只金色叙利亚仓鼠(Mesocricetus auratus)在诱导冬眠(冬眠)和恒温(非冬眠)状态下的脑组织,通过定量多种磷酸化和非磷酸化的tau肽,使用先前应用于人脑组织的IP-MS方法。在棕熊中,与夏季相比,冬眠期间血浆中磷酸化tau (p-tau)生物标志物p-tau181和p-tau217的水平显著增加(IP-MS的中位数分别增加了362%和294%),免疫测定也发现了类似的增加。与AD病理相关的其他血浆p-tau生物标志物,包括p-tau205和p-tau231,在熊冬眠期间也有所增加。在仓鼠大脑中,p-tau217和p-tau231在冬眠期间同样升高,而与缠结聚集相关的微管结合区(MTBR)的tau片段没有增加。相比之下,用相同的IP-MS方法分析n = 10名AD患者的脑组织,与n = 10名人类对照相比,p-tau (p-tau217)和MTBR片段(MTBR tau354-369)显著增加(~ 50,000%)。我们发现冬眠相关的tau过度磷酸化涉及AD中一些相同的磷酸化位点的改变,但没有MTBR tau聚集。这突出了冬眠作为一种可逆的、非病理的模型来研究AD的tau生物学和机制,因为冬眠的可逆性和缺乏tau聚集,尽管AD的关键tau磷酸化位点过度磷酸化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Reversible tau hyperphosphorylation in hibernation: a blood biomarker and brain tissue study

Tau hyperphosphorylation, a key neuropathological feature of tauopathies such as Alzheimer’s disease (AD), also occurs physiologically during mammalian hibernation and is fully reversed upon arousal, offering a unique translational model to study tau metabolism. However, limited data exist on insoluble and soluble tau alterations during hibernation and on patterns of tau fragment concentrations in the hibernating mammalian brain. We quantified tau biomarkers in plasma samples from ten free-ranging brown bears (Ursus arctos), captured during both their active summer period and hibernation in the winter, using clinically validated immunoassays and immunoprecipitation mass spectrometry (IP-MS) techniques. We also analyzed brain tissue from ten golden Syrian hamsters (Mesocricetus auratus) subjected to induced torpor (hibernation) versus euthermic (non-hibernating) states by quantifying multiple phosphorylated and non-phosphorylated tau peptides with an IP-MS method previously applied in human brain tissue. In brown bears, plasma levels of phosphorylated tau (p-tau) biomarkers p-tau181 and p-tau217 significantly increased during hibernation compared to summer (median increases of 362% and 294% by IP-MS, respectively), with similar increases found with immunoassays. Additional plasma p-tau biomarkers associated with AD pathology, including p-tau205 and p-tau231, were also increased during bear hibernation. In hamster brains, p-tau217, and p-tau231 were similarly elevated during torpor, while tau fragments from the microtubule-binding region (MTBR), associated with tangle aggregation, were not increased. In contrast, brain tissue from n = 10 AD patients, analyzed with the same IP-MS method, exhibited striking increases in p-tau (~ 50,000% for p-tau217) and MTBR fragments (~ 20,000% for MTBR tau354-369) compared with n = 10 human controls. We show that hibernation-linked tau hyperphosphorylation involves some of the same phospho-sites altered in AD, but occurs without MTBR tau aggregation. This highlights hibernation as a reversible, non-pathological model to study tau biology and mechanisms underlying AD due to its reversibility and lack of tau aggregation despite hyperphosphorylation in key AD tau phospho-sites.

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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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