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Kinetic data, oligomer data and binding data

Citation

Linse, Sara et al. (2020), Kinetic data, oligomer data and binding data, Dryad, Dataset, https://doi.org/10.5061/dryad.79cnp5hsn

Abstract

The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer’s disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess.  Here, we combine kinetic analyses with quantitative binding measurements to address the mechanisms of action of four clinical stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates, and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ.  Our results reveal that, uniquely amongst these four antibodies, aducanumab dramatically reduces the flux of Aβ oligomers.

Methods

Thioflavin T fluorescence, analysed uing Amylofit database

Mass spectrometry after aggregation to t-half, centrifugation to remove fibrils and SEC to isolate oligomers

Microfulidic diffusion sizing of Alexa647-labelled species with increaseing conenctration of ligand

Funding

Swedish Research Council , Award: 2015-00143

European Research Council, Award: 340890

Knut and Alice Wallenberg Foundation , Award: 2016.0074

Novo Nordisk Foundation, Award: NNF19OC0054635

Swedish Research Council, Award: 2015-00143

Knut and Alice Wallenberg Foundation, Award: 2016.0074