Distinct amyloid-β filament fold in individuals with APP Flemish mutation

Area of Science:

• Neuroscience
• Structural Biology
• Genetics

Background:

• The Flemish mutation (A692G in APP, A21G in Aβ) causes a rare, early-onset Alzheimer disease.
• This variant is characterized by severe cerebral amyloid angiopathy and large senile plaque cores.

Purpose of the Study:

• To determine the structural basis of amyloid filament formation in Flemish Alzheimer disease.
• To elucidate the molecular mechanisms underlying the vascular tropism observed in this familial Alzheimer disease variant.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structure of amyloid filaments from postmortem brain tissue.
• Cell-based assays were employed to investigate the functional consequences of the Flemish fold.

Main Results:

• The predominant amyloid filaments consist of Aβ40 with the A21G substitution, adopting a novel 'Flemish fold' with a unique hydrophobic interface.
• This Flemish fold differs from previously characterized amyloid-β folds and is associated with vascular tropism.
• While tau filaments were present, Aβ40-A21G filaments were the predominant species.

Conclusions:

• The study defines a novel familial Alzheimer disease-associated amyloid fold, the Flemish fold.
• This fold provides structural insight into the pathogenesis of Flemish-type dementia, including cerebral amyloid angiopathy and hemorrhage.