Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting

Marie P. Schützmann, Filip Hasecke, Sarah Bachmann, Mara Zielinski, Sebastian Hänsch, Gunnar F. Schröder, Hans Zempel () and Wolfgang Hoyer ()
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Marie P. Schützmann: Heinrich-Heine-Universität Düsseldorf
Filip Hasecke: Heinrich-Heine-Universität Düsseldorf
Sarah Bachmann: University of Cologne, Faculty of Medicine and University Hospital Cologne
Mara Zielinski: Forschungszentrum Jülich
Sebastian Hänsch: Heinrich-Heine-Universität Düsseldorf
Gunnar F. Schröder: Forschungszentrum Jülich
Hans Zempel: University of Cologne, Faculty of Medicine and University Hospital Cologne
Wolfgang Hoyer: Heinrich-Heine-Universität Düsseldorf

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Amyloid-β peptide (Aβ) forms metastable oligomers >50 kDa, termed AβOs, that are more effective than Aβ amyloid fibrils at triggering Alzheimer’s disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aβ accumulates in endo-lysosomal vesicles at low pH. Here, we show that 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 the dimeric Aβ variant 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.

Date: 2021
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DOI: 10.1038/s41467-021-24900-4

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