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Brain aging is faithfully modelled in organotypic brain slices and accelerated by prions


Liu, Yingjun; Senatore, Assunta; Sorce, Silvia; Nuvolone, Mario; Guo, Jingjing; Gümüş, Zeynep H; Aguzzi, Adriano (2022). Brain aging is faithfully modelled in organotypic brain slices and accelerated by prions. Communications Biology, 5(1):557.

Abstract

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.

Abstract

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Medicine (miscellaneous)
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Life Sciences > General Agricultural and Biological Sciences
Uncontrolled Keywords:General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology, Medicine (miscellaneous)
Language:English
Date:1 December 2022
Deposited On:21 Jun 2022 15:23
Last Modified:27 Apr 2024 01:38
Publisher:Nature Publishing Group
ISSN:2399-3642
Additional Information:A correction of this article has been published on 20 June 2022 regarding a missing grant number of the SNSF: Liu, Y., Senatore, A., Sorce, S. et al. Author Correction: Brain aging is faithfully modelled in organotypic brain slices and accelerated by prions. Commun Biol 5, 609 (2022). https://doi.org/10.1038/s42003-022-03572-w
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s42003-022-03496-5
Related URLs:https://doi.org/10.1038/s42003-022-03572-w (Publisher)
PubMed ID:35676449
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_179040
  • : Project TitleThe prion protein in health and disease
  • : FunderEuropean Research Council
  • : Grant ID
  • : Project Title
  • : FunderNomis Foundation
  • : Grant ID
  • : Project Title
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)