Journal article Open Access

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

Ruth E. Uhlmann1,2,3,*, Christine Rother1,2,3,*, Jay Rasmussen1,2,3, Juliane Schelle1,2, Carina Bergmann1, Emily M. Ullrich Gavilanes1,3, Sarah K. Fritschi1,2, Anika Buehler1,2, Frank Baumann1,2, Angelos Skodras1,2, Rawaa Al-Shaana1,2, Natalie Beschorner1,2, Lan Ye1,2, Stephan A. Kaeser1,2, Ulrike Obermüller1,2, Søren Christensen4, Fredrik Kartberg4, Jeffrey B. Stavenhagen4, Jens-Ulrich Rahfeld5, Holger Cynis5, Fang Qian6, Paul H. Weinreb6, Thierry Bussiere6, Lary C. Walker7, Matthias Staufenbiel1, Mathias Jucker1,2

Ab deposits are a relatively late consequence of Ab aggregation in Alzheimer´s disease (AD). It is not known when pathogenic Ab seeds begin to form, propagate, and spread, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Ab seeds before b-amyloid deposition becomes detectable in Ab-precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Ab assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Ab deposition and downstream pathologies 6 months later. This demonstrates therapeutically targetable pathogenic Ab seeds already exist during the lag-phase of protein aggregation in brain. Thus, the preclinical phase of AD – currently defined as Ab 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.

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