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@ARTICLE{PeraltaReyes:1044126,
author = {Peralta Reyes, Fernanda S. and Sommerhage, Simon and
Willbold, Dieter and Schröder, Gunnar F. and Gremer,
Lothar},
title = {{L}ecanemab {B}inds to {T}ransgenic {M}ouse
{M}odel‐{D}erived {A}myloid‐β {F}ibril {S}tructures
{R}esembling {A}lzheimer's {D}isease {T}ype {I}, {T}ype {II}
and {A}rctic {F}olds},
journal = {Neuropathology $\&$ applied neurobiology},
volume = {51},
number = {3},
issn = {0305-1846},
address = {Oxford [u.a.]},
publisher = {Wiley-Blackwell},
reportid = {FZJ-2025-03033},
pages = {e70022},
year = {2025},
abstract = {Aims:Lecanemab, an Alzheimer’s disease US Food and Drug
Administration-approved monoclonal antibody, was previously
reported to have a high affinity against intermediately
sized amyloid-β aggregates. Subsequently, it was observed
by immunogold labelling that lecanemab can also bind to
human type I amyloid-β fibrils. To determine whether
lecanemab binds to amyloid-β fibril structures other than
type I, we analysed its binding capacity to various
structurally defined and pathologically relevant amyloid-β
fibrils.Methods:We performed immunogold labelling with
lecanemab on extracted amyloid-β fibril preparations from
six different Alzheimer´s disease mouse models whose
structures were previously solved by cryo-EM and quantified
the relative binding affinities of lecanemab to the
different fibril polymorphs.Results:Our results show that
lecanemab exhibits high binding affinity to amyloid-β
fibril structures that have a flexible N-terminus in common,
as is the case for type I, type II and murine type III
amyloid-β fibril polymorphs, which resemble or are
identical to human structures observed in sporadic and
familial cases of Alzheimer’s disease, including a case
with the Arctic (E22G) mutation. In contrast, only weak
lecanemab binding was observed for murine amyloid-β fibrils
with a fixed and ordered N-terminus.Conclusions:These
findings may also explain the low incidence of ARIA-E with
lecanemab in clinical trials. This is because human
meningeal amyloid-β fibrils derived from cerebral amyloid
angiopathy affected brain tissue also contain a fixed and
ordered N-terminus, most likely preventing lecanemab
binding.},
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},
pubmed = {40495448},
UT = {WOS:001507890600001},
doi = {10.1111/nan.70022},
url = {https://juser.fz-juelich.de/record/1044126},
}