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

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 Salvadori, Maarten Loos, Irena Brzak, Derya Shimshek, Ulf Neumann, Lary C. Walker, Stephanie A. Schultz, Jasmeer P. Chhatwal, Stephan A. Kaeser, Stefan F. Lichtenthaler, Matthias Staufenbiel and Mathias Jucker ()
Additional contact information
Christine Rother: University of Tübingen
Ruth E. Uhlmann: University of Tübingen
Stephan A. Müller: German Center for Neurodegenerative Diseases (DZNE)
Juliane Schelle: University of Tübingen
Angelos Skodras: University of Tübingen
Ulrike Obermüller: University of Tübingen
Lisa M. Häsler: University of Tübingen
Marius Lambert: University of Tübingen
Frank Baumann: University of Tübingen
Ying Xu: University of Tübingen
Carina Bergmann: University of Tübingen
Giulia Salvadori: University of 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
Stefan F. Lichtenthaler: German Center for Neurodegenerative Diseases (DZNE)
Matthias Staufenbiel: University of Tübingen
Mathias Jucker: University of Tübingen

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34538-5

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