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@ARTICLE{Zielinski:1047078,
author = {Zielinski, Mara and Peralta Reyes, Fernanda S. and Gremer,
Lothar and Sommerhage, Simon and Pagnon de la Vega, María
and Röder, Christine and Heidler, Thomas V. and Syvänen,
Stina and Willbold, Dieter and Sehlin, Dag and Ingelsson,
Martin and Schröder, Gunnar F.},
title = {{C}ryo-{EM} studies of amyloid-β fibrils from human and
murine brains carrying the {U}ppsala {APP} mutation
(Δ690–695)},
journal = {Acta Neuropathologica Communications},
volume = {13},
number = {1},
issn = {2051-5960},
address = {London},
publisher = {Biomed Central},
reportid = {FZJ-2025-04104},
pages = {209},
year = {2025},
abstract = {Today, 13 intra-amyloid-β (Aβ) amyloid precursor protein
(APP) gene mutations are known to cause familial
Alzheimer’s disease (AD). Most of them are point mutations
causing an increased production or a change in the
conformation of Aβ. The Uppsala APP mutation (Δ690–695
in APP, Δ19–24 in Aβ) is the first known multi-codon
deletion causing autosomal dominant AD. Here, we applied
cryo-electron microscopy (cryo-EM) to investigate the
structure of Aβ fibrils with the Uppsala APP mutation from
tg-UppSwe mouse brain tissue. Murine AβUpp(1–42)Δ19–24
are made of two identical S-shaped protofilaments with an
ordered fibril core of S8-A42. The murine Aβ fold is almost
identical to previously described human type II filaments,
although the amino acid sequences differ considerably. In
addition, we report the cryo-EM structure of Aβ fibrils
from the temporal cortex of a patient with the Uppsala APP
mutation. The observed structure of the human Aβ fold
closely resembles previously described type I fibrils.
Structural modeling suggests that these fibrils are composed
of wild-type Aβ, which implies that AβUpp may be less
soluble and thus not readily accessible for cryo-EM image
processing and structure determination. Additionally, from
the human sample we determined the structures of tau paired
helical filaments and tau straight filaments, which are
identical to those found in sporadic AD cases. Finally, we
present the 3D cryo-EM structures of four dominant
AβUpp(1–42)Δ19–24 fibril polymorphs, formed in vitro.
All four polymorphs differ from the observed folds of
Uppsala Aβ in murine and human brain tissue, respectively.},
cin = {IBI-7},
ddc = {610},
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},
doi = {10.1186/s40478-025-02120-x},
url = {https://juser.fz-juelich.de/record/1047078},
}