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| Home > Publications database > Lecanemab Binds to Transgenic Mouse Model‐Derived Amyloid‐β Fibril Structures Resembling Alzheimer's Disease Type I, Type II and Arctic Folds |
| Home > Publications database > Lecanemab Binds to Transgenic Mouse Model‐Derived Amyloid‐β Fibril Structures Resembling Alzheimer's Disease Type I, Type II and Arctic Folds |
| Journal Article | FZJ-2025-03033 |
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2025
Wiley-Blackwell
Oxford [u.a.]
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Please use a persistent id in citations: doi:10.1111/nan.70022 doi:10.34734/FZJ-2025-03033
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.
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