Universität zu Köln

Schutzmann, Marie P., Hasecke, Filip, Bachmann, Sarah, Zielinski, Mara, Haensch, Sebastian, Schroeder, Gunnar F., Zempel, Hans and Hoyer, Wolfgang ORCID: 0000-0003-4301-5416 (2021). Endo-lysosomal A beta concentration and pH trigger formation of A beta oligomers that potently induce Tau missorting. Nat. Commun., 12 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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Abstract

Amyloid-beta peptide (A beta) forms metastable oligomers >50 kDa, termed A beta Os, that are more effective than A beta amyloid fibrils at triggering Alzheimer's disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, A beta accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of A beta O 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 A beta O formation and the high endo-lysosomal A beta concentration together enable extensive A beta O formation of A beta 42 under physiological conditions. Exploiting the enhanced A beta O formation of the dimeric A beta variant dimA beta we furthermore demonstrate targeting of A beta Os 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 A beta Os. A beta oligomers (A beta O) are thought to represent the main toxic species in Alzheimer's disease but very high A beta concentrations are required to study them in vitro and it remains unknown what role these off-pathway oligomers play in vivo. Here, the authors use a dimeric variant of A beta termed dimA beta, where two A beta 40 units are linked, which facilitates to study A beta O formation kinetics and they observe that A beta off-pathway oligomer formation is strongly accelerated at endo-lysosomal pH, while amyloid fibril formation is delayed. Furthermore, the authors demonstrate that dimA beta is a disease-relevant model construct for pathogenic A beta O formation by showing that dimA beta A beta Os target dendritic spines and induce AD-like somatodendritic Tau missorting.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schutzmann, Marie P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hasecke, Filip UNSPECIFIED UNSPECIFIED UNSPECIFIED Bachmann, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Zielinski, Mara UNSPECIFIED UNSPECIFIED UNSPECIFIED Haensch, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Gunnar F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zempel, Hans UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoyer, Wolfgang UNSPECIFIED orcid.org/0000-0003-4301-5416 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-584425
DOI:	10.1038/s41467-021-24900-4
Journal or Publication Title:	Nat. Commun.
Volume:	12
Number:	1
Date:	2021
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language AMYLOID-BETA; ALZHEIMERS-DISEASE; PROTEIN FIBRILLOGENESIS; MOLECULAR-BASIS; MOUSE MODEL; NEUROTOXICITY; A-BETA(1-42); AGGREGATION; PHOSPHORYLATION; VISUALIZATION Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58442