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Пишет bioRxiv Subject Collection: Neuroscience (![[info]](http://lj.rossia.org/img/syndicated.gif){kind=small} syn_bx_neuro)@ 2025-01-19 05:42:00 |
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Lecanemab binds to transgenic mouse model-derived amyloid-β fibril structures resembling Alzheimer 's disease type-I, type-II and Arctic folds
Lecanemab, an Alzheimers disease US Food and Drug Administration approved monoclonal antibody was previously reported to have a high affinity against intermediately sized amyloid-{beta} aggregates. Subsequently, it was observed by immunogold labelling that lecanemab can also bind to human type-I amyloid-{beta} fibrils. Therefore, to determine whether lecanemab binds to amyloid-{beta} fibril structures other than type-I, we performed immunogold labelling on extracted amyloid-{beta} fibril preparations from six different Alzheimers disease mouse models whose structures were previously solved by cryo-EM. Our results show that lecanemab exhibits high binding affinity to amyloid-{beta} fibril structures that have a flexible N-terminus in common, as it is the case for type-I, type-II and murine type-III amyloid-{beta} fibril polymorphs which resemble or are identical to human structures observed in sporadic and familial cases of Alzheimers disease, including a case with the Arctic (E22G) mutation. In contrast, only weak, if any, lecanemab binding was observed for amyloid-{beta} fibril folds with a fixed and ordered N-terminus.
Key points- Lecanemab binds to A{beta} fibrils from several Alzheimers disease tg-mice whose structures resemble the type-I, type-II and Arctic folds found in Alzheimers patients, all of which share a flexible, unstructured N-terminus.
- Lecanemab is therefore expected to be active against all common familial and sporadic Alzheimers cases containing these folds.
- Lecanemab binding ability is unaffected by and tolerates the Arctic E22G mutation, at least in type-I or Arctic folds.
- Weak, if any, lecanemab binding was observed to A{beta} fibrils derived from tg-SwDI mice, whose structures DI1, DI2 and DI3 all share structured and fixed N-termini.
- Since the fixed N-termini of tg-SwDI DI1 fibrils and human meningeal A{beta}40 fibrils derived from CAA-affected brain are identical, most likely preventing lecanemab binding, treatment with lecanemab may be less or ineffective against CAA, but may explain the reported beneficial low ARIA-E frequency with this antibody.
Table of Contents Graphic (TOC)
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/633637v1_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@dacc05org.hig
Lecanemab, an Alzheimers disease US Food and Drug Administration approved monoclonal antibody was previously reported to have a high affinity against intermediately sized amyloid-{beta} aggregates. Subsequently, it was observed by immunogold labelling that lecanemab can also bind to human type-I amyloid-{beta} fibrils. Therefore, to determine whether lecanemab binds to amyloid-{beta} fibril structures other than type-I, we performed immunogold labelling on extracted amyloid-{beta} fibril preparations from six different Alzheimers disease mouse models whose structures were previously solved by cryo-EM. Our results show that lecanemab exhibits high binding affinity to amyloid-{beta} fibril structures that have a flexible N-terminus in common, as it is the case for type-I, type-II and murine type-III amyloid-{beta} fibril polymorphs which resemble or are identical to human structures observed in sporadic and familial cases of Alzheimers disease, including a case with the Arctic (E22G) mutation. In contrast, only weak, if any, lecanemab binding was observed for amyloid-{beta} fibril folds with a fixed and ordered N-terminus.
Key points- Lecanemab binds to A{beta} fibrils from several Alzheimers disease tg-mice whose structures resemble the type-I, type-II and Arctic folds found in Alzheimers patients, all of which share a flexible, unstructured N-terminus.
- Lecanemab is therefore expected to be active against all common familial and sporadic Alzheimers cases containing these folds.
- Lecanemab binding ability is unaffected by and tolerates the Arctic E22G mutation, at least in type-I or Arctic folds.
- Weak, if any, lecanemab binding was observed to A{beta} fibrils derived from tg-SwDI mice, whose structures DI1, DI2 and DI3 all share structured and fixed N-termini.
- Since the fixed N-termini of tg-SwDI DI1 fibrils and human meningeal A{beta}40 fibrils derived from CAA-affected brain are identical, most likely preventing lecanemab binding, treatment with lecanemab may be less or ineffective against CAA, but may explain the reported beneficial low ARIA-E frequency with this antibody.
Table of Contents Graphic (TOC)
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/633637v1_ufig1.gif" ALT="Figure 1">
View larger version (27K):
org.highwire.dtl.DTLVardef@dacc05org.hig
