Journal Article

FZJ-2021-05893

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting

Schützmann, M. P. ; Hasecke, F. ; Bachmann, S. ; Zielinski, M.FZJ* ; Hänsch, S. ; Schröder, G. F.FZJ* ; Zempel, H. (Corresponding author) ; Hoyer, W. (Corresponding author)FZJ*

2021
Nature Publishing Group UK [London]

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Please use a persistent id in citations: http://hdl.handle.net/2128/29691  doi:10.1038/s41467-021-24900-4

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.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 5244 - Information Processing in Neuronal Networks (POF4-524) (POF4-524)

Appears in the scientific report 2021

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