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Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

Author

Listed:
  • Christine Rother

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen
    University of Tübingen)

  • Ruth E. Uhlmann

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen
    University of Tübingen)

  • Stephan A. Müller

    (German Center for Neurodegenerative Diseases (DZNE)
    Technical University of Munich
    Munich Cluster for Systems Neurology (SyNergy))

  • Juliane Schelle

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen)

  • Angelos Skodras

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen)

  • Ulrike Obermüller

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen)

  • Lisa M. Häsler

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen)

  • Marius Lambert

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen)

  • Frank Baumann

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen)

  • Ying Xu

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen)

  • Carina Bergmann

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen
    University of Tübingen)

  • Giulia Salvadori

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen)

  • Maarten Loos

    (Sylics (Synaptologics BV))

  • Irena Brzak

    (Novartis Institutes for Biomedical Research)

  • Derya Shimshek

    (Novartis Institutes for Biomedical Research)

  • Ulf Neumann

    (Novartis Institutes for Biomedical Research)

  • Lary C. Walker

    (Emory University)

  • Stephanie A. Schultz

    (Massachusetts General Hospital)

  • Jasmeer P. Chhatwal

    (Massachusetts General Hospital)

  • Stephan A. Kaeser

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen)

  • Stefan F. Lichtenthaler

    (German Center for Neurodegenerative Diseases (DZNE)
    Technical University of Munich
    Munich Cluster for Systems Neurology (SyNergy))

  • Matthias Staufenbiel

    (University of Tübingen)

  • Mathias Jucker

    (University of Tübingen
    German Center for Neurodegenerative Diseases (DZNE), Tübingen)

Abstract

Brain Aβ deposition is a key early event in the pathogenesis of Alzheimer´s disease (AD), but the long presymptomatic phase and poor correlation between Aβ deposition and clinical symptoms remain puzzling. To elucidate the dependency of downstream pathologies on Aβ, we analyzed the trajectories of cerebral Aβ accumulation, Aβ seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in Aβ-precursor protein transgenic mice. We find that Aβ deposition increases linearly until it reaches an apparent plateau at a late age, while Aβ seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of Aβ generation in amyloid-laden mice reduced Aβ deposition and associated glial changes, but failed to reduce Aβ seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of Aβ generation was started at pre-amyloid stages, CSF NfL did not increase despite some Aβ deposition, microglial activation, and robust brain Aβ seeding activity. A dissociation of Aβ load and CSF NfL trajectories was also found in familial AD, consistent with the view that Aβ aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when Aβ seeding activity is saturated and before Aβ deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease.

Suggested Citation

  • Christine Rother & Ruth E. Uhlmann & Stephan A. Müller & Juliane Schelle & Angelos Skodras & Ulrike Obermüller & Lisa M. Häsler & Marius Lambert & Frank Baumann & Ying Xu & Carina Bergmann & Giulia Sa, 2022. "Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34538-5
    DOI: 10.1038/s41467-022-34538-5
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    References listed on IDEAS

    as
    1. Mathias Jucker & Lary C. Walker, 2013. "Self-propagation of pathogenic protein aggregates in neurodegenerative diseases," Nature, Nature, vol. 501(7465), pages 45-51, September.
    2. Malin K. Sandberg & Huda Al-Doujaily & Bernadette Sharps & Anthony R. Clarke & John Collinge, 2011. "Prion propagation and toxicity in vivo occur in two distinct mechanistic phases," Nature, Nature, vol. 470(7335), pages 540-542, February.
    3. John Collinge, 2016. "Mammalian prions and their wider relevance in neurodegenerative diseases," Nature, Nature, vol. 539(7628), pages 217-226, November.
    4. Eric McDade & Randall J. Bateman, 2017. "Stop Alzheimer’s before it starts," Nature, Nature, vol. 547(7662), pages 153-155, July.
    Full references (including those not matched with items on IDEAS)

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