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

Rother, Christine; Uhlmann, Ruth E.; Mueller, Stephan A.; Schelle, Juliane; Skodras, Angelos; Obermuller, Ulrike; Hasler, Lisa M.; Lambert, Marius; Baumann, Frank; Xu, Ying; Bergmann, Carina; Salvadori, Giulia; Loos, Maarten; Brzak, Irena; Shimshek, Derya; Neumann, Ulf; Walker, Lary C.; Schultz, Stephanie A.; Chhatwal, Jasmeer P.; Kaeser, Stephan A.; Lichtenthaler, Stefan F.; Staufenbiel, Matthias und Jucker, Mathias (2022): Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae. In: Nature Communications, Bd. 13, Nr. 1, 7333

Abstract

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

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198