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@ARTICLE{Schtzmann:904323,
author = {Schützmann, Marie P. and Hasecke, Filip and Bachmann,
Sarah and Zielinski, Mara and Hänsch, Sebastian and
Schröder, Gunnar F. and Zempel, Hans and Hoyer, Wolfgang},
title = {{E}ndo-lysosomal {A}β concentration and p{H} trigger
formation of {A}β oligomers that potently induce {T}au
missorting},
journal = {Nature Communications},
volume = {12},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {FZJ-2021-05893},
pages = {4634},
year = {2021},
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.},
cin = {IBI-7},
ddc = {500},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {5244 - Information Processing in Neuronal Networks
(POF4-524)},
pid = {G:(DE-HGF)POF4-5244},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:34330900},
UT = {WOS:000684302900001},
doi = {10.1038/s41467-021-24900-4},
url = {https://juser.fz-juelich.de/record/904323},
}