Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life

• Authors: Ruth E Uhlmann, University of Tübingen; Christine Rother, University of Tübingen; Jay Rasmussen, University of Tübingen; Juliane Schelle, University of Tübingen; Carina Bergmann, University of Tübingen; Emily M Ullrich Gavilanes, University of Tübingen; Sarah K Fritschi, University of Tübingen; Anika Buehler, University of Tübingen; Frank Baumann, University of Tübingen; Angelos Skodras, University of Tübingen; Rawaa Al-Shaana, University of Tübingen; Natalie Beschorner, University of Tübingen; Lan Ye, University of Tübingen; Stephan A Kaeser, University of Tübingen; Ulrike Obermueller, University of Tübingen; Søren Christensen, H Lundbeck & Co AS; Fredrik Kartberg, H Lundbeck & Co AS; Jeffrey B Stavenhagen, H Lundbeck & Co AS; Jens-Ulrich Rahfeld, Fraunhofer Institute for Cell Therapy and Immunology; Holger Cynis, Fraunhofer Institute for Cell Therapy and Immunology; Fang Qian, Biogen Inc; Paul H Weinreb, Biogen Inc; Thierry Bussiere, Biogen Inc; Lary Walker, Emory University; Matthias Staufenbiel, University of Tübingen; Mathias Jucker, University of Tübingen
• Journal Title: NATURE NEUROSCIENCE
• Volume: Volume 23, Number 12
• Publisher: NATURE RESEARCH | 2020-11-16, Pages 1580-U91
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/s41593-020-00737-w
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; A-BETA SEEDS; MOUSE MODEL; DISEASE; DEPOSITION; ANTIBODY; CSF; ACCUMULATION; ASSOCIATION; INDUCTION; PLAQUES

Abstract

Amyloid-β (Aβ) deposits are a relatively late consequence of Aβ aggregation in Alzheimer‘s disease. When pathogenic Aβ seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Aβ seeds before Aβ deposition becomes detectable in Aβ precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Aβ assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Aβ deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer‘s disease—currently defined as Aβ deposition without clinical symptoms—may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.