Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Commun Biol. 2022 Jun 8;5(1):557. doi: 10.1038/s42003-022-03496-5.
Mammalian models are essential for brain aging research. However, the long lifespan and poor amenability to genetic and pharmacological perturbations have hindered the use of mammals for dissecting aging-regulatory molecular networks and discovering new anti-aging interventions. To circumvent these limitations, we developed an ex vivo model system that faithfully mimics the aging process of the mammalian brain using cultured mouse brain slices. Genome-wide gene expression analyses showed that cultured brain slices spontaneously upregulated senescence-associated genes over time and reproduced many of the transcriptional characteristics of aged brains. Treatment with rapamycin, a classical anti-aging compound, largely abolished the time-dependent transcriptional changes in naturally aged brain slice cultures. Using this model system, we discovered that prions drastically accelerated the development of age-related molecular signatures and the pace of brain aging. We confirmed this finding in mouse models and human victims of Creutzfeldt-Jakob disease. These data establish an innovative, eminently tractable mammalian model of brain aging, and uncover a surprising acceleration of brain aging in prion diseases.
哺乳动物模型在脑衰老研究中至关重要。然而，由于寿命长且遗传和药理学干扰的适应性差，限制了哺乳动物在解析衰老调节分子网络和发现新的抗衰老干预措施方面的应用。为了克服这些限制，我们开发了一种离体模型系统，该系统使用培养的鼠脑切片忠实地模拟了哺乳动物大脑的衰老过程。全基因组基因表达分析表明，培养的脑切片随时间自发地上调衰老相关基因，并复制了许多老年大脑的转录特征。雷帕霉素是一种经典的抗衰老化合物，它的处理在很大程度上消除了天然衰老脑切片培养物中随时间变化的转录变化。使用该模型系统，我们发现朊病毒极大地加速了与年龄相关的分子特征的发展和大脑衰老的速度。我们在小鼠模型和克雅氏病的人类受害者中证实了这一发现。这些数据建立了一种创新的、易于研究的哺乳动物大脑衰老模型，并揭示了朊病毒病中大脑衰老的惊人加速。
