Short talk:
Metastable amyloid-β oligomers – Kinetics, mechanisms, interactions

Marie Schützmann1, Filip Hasecke2, Sarah Bachmann3, Mara Zielinski4, Sebastian Hänsch5, Gunnar F. Schröder4, Hans Zempel3, Wolfgang Hoyer2

1Heinrich Heine University Düsseldorf, Institut für Physikalische Biologie, Düsseldorf, Germany,
2Heinrich Heine University Düsseldorf, Institut für Physikalische Biologie, Düsseldorf, Germany,
3University of Cologne, Institute of Human Genetics and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany,
4Forschungszentrum Jülich, Institute of Biological Information Processing (IBI-7), Jülich, Germany,
5Heinrich Heine University Düsseldorf, Department of Biology, Center for Advanced Imaging (CAi), Düsseldorf, Germany

Metastable oligomers of amyloid-β peptide (Aβ) are more effective than Aβ amyloid fibrils at triggering Alzheimer’s disease-related processes such as synaptic dysfunction and Tau pathology. Here we elucidate the mechanism of Aβ oligomer (AβO) formation and identify physiological conditions that promote AβO generation. AβO formation was determined utilizing Aβ42 as well as the dimeric Aβ construct dimAβ that facilitates analysis of the oligomerization kinetics. AβO formation, clustering, and release were imaged by atomic force microscopy. The structure of the smallest AβOs was investigated by cryo-EM. The capacity of AβOs to bind to dendritic spines, to induce Tau missorting, and to impair neuronal function were studied in primary mouse neuronal cell cultures. The rate of AβO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endo-lysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AβO formation and the high endo-lysosomal Aβ concentration together enable extensive AβO formation of Aβ42 under physiological conditions. Exploiting the enhanced AβO formation of dimAβ we furthermore demonstrate targeting of AβOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AβOs.

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