Experimental evidence for temporal uncoupling of brain Abeta deposition and neurodegenerative sequelae.

Abstract:

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

SEEK ID: http://localhost:3000/publications/17

PubMed ID: 36443293

Projects: Published Datasets

Publication type: Journal

Journal: Nat Commun

Citation: Nat Commun. 2022 Nov 28;13(1):7333. doi: 10.1038/s41467-022-34538-5.

Date Published: 28th Nov 2022

Registered Mode: by PubMed ID

Authors: C. Rother, R. E. Uhlmann, S. A. Muller, J. Schelle, A. Skodras, U. Obermuller, L. M. Hasler, M. Lambert, F. Baumann, Y. Xu, C. Bergmann, G. Salvadori, M. Loos, I. Brzak, D. Shimshek, U. Neumann, L. C. Walker, S. A. Schultz, J. P. Chhatwal, S. A. Kaeser, S. F. Lichtenthaler, M. Staufenbiel, M. Jucker

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Created: 5th Jul 2024 at 09:27

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