Title: Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life
Author: Ruth E. Uhlmann, Christine Rother, Jay Rasmussen, Juliane Schelle, Carina Bergmann, Emily M. Ullrich Gavilanes, Sarah K. Fritschi, Anika Buehler, Frank Baumann, Angelos Skodras, Rawaa Al-Shaana, Natalie Beschorner, Lan Ye, Stephan A. Kaeser, Ulrike Obermller, Sren Christensen, Fredrik Kartberg, Jeffrey B. Stavenhagen, Jens-Ulrich Rahfeld, Holger Cynis, Fang Qian, Paul H. Weinreb, Thierry Bussiere, Lary C. Walker, Matthias Staufenbiel, Mathias Jucker
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.