9WTW

Amyloid-beta 40 Flemish (A21G) mutant Filaments from Human Brain

Summary for 9WTW

• Entry DOI: 10.2210/pdb9wtw/pdb
• EMDB information: 66225
• Descriptor: Amyloid-beta protein 40 (2 entities in total)
• Functional Keywords: amyloid-beta, alzheimer's disease, neurodegeneration, protein aggregation, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 10
• Total formula weight: 43218.26

Authors

Guillen-Poza, P.A.,Yang, Y.,Hervas, R. (deposition date: 2025-09-17, release date: 2026-08-05, Last modification date: 2026-08-26)

Primary citation

Khaki, P.S.S.,Guillen-Poza, P.A.,Wong, C.,Kan, C.,Sharma, R.,Sugimura, R.,Robinson, A.C.,Valbuena, A.,Ng, R.C.,Yang, Y.,Hervas, R.
Distinct amyloid-beta filament fold in individuals with APP Flemish mutation.
Nat.Struct.Mol.Biol., 33:1194-1203, 2026

PubMed Abstract: The dominantly inherited Flemish mutation-an A692G substitution in the amyloid precursor protein, corresponding to an A21G change in amyloid-β (Aβ)-causes a rare, early-onset form of Alzheimer disease characterized by pronounced cerebral amyloid angiopathy and unusually large senile plaque cores. Here, we report cryo-electron microscopy structures of amyloid filaments extracted from the postmortem parietal lobes of two individuals representing the only two known Flemish pedigrees worldwide. Although tau paired helical filaments were present, the predominant filaments comprise Aβ40-A21G, assembled as two identical protofilaments (D1-V40) packed with two-start helical symmetry. Aβ40-A21G and wild-type Aβ42 filaments share a substructure preceding the substitution site (Y10-F19); however, loss of the methyl group at residue 21 gives rise to a distinct arrangement, termed the 'Flemish fold', which differs from all previously characterized Aβ folds and is defined by a unique hydrophobic interface. Using a cell-based assay, we find that this distinctive fold is associated with the vascular tropism characteristic of the Flemish variant. Together, our structural and cellular data define a familial Alzheimer-disease-associated amyloid fold and provide insight into the molecular basis of Flemish-type dementia and cerebral hemorrhage.

PubMed: 42562893
DOI: 10.1038/s41594-026-01855-y

Experimental method

ELECTRON MICROSCOPY (1.98 Å)