Structural basis of synthetic Aβ fibrils with Flemish or Italian mutations

The deposition of β-amyloid (Aβ) in the brains is considered a key factor in the pathogenesis of Alzheimer’s Diseases (AD), as supported by the link between Aβ mutations and familiar AD (FAD). More than ten Aβ mutations have been identified as causative for FAD, yet the molecular architectures of fibrils formed by most of these mutants remain elusive. In this study, we report the cryo-EM structures of Aβ fibrils formed by the Flemish (A21G) and Italian (E22K) mutants at resolutions of 3.1 - 4.0 Å. Aβ42A21G fibrils exhibit four morphologies comprising two distinct conformations, whereas Aβ42 E22K fibrils display a single morphology with a unique fold stabilized by salt bridges involving Lys22. Despite these structural differences, the oligomeric forms of both mutants are recognized by the natural neuronal Aβ receptor LilrB2. Our findings provide molecular insights into how disease-relevant mutations affect Aβ aggregation, with potential implications for the development of therapeutics and diagnostics for corresponding FAD subtypes. More than ten β-amyloid (Aβ) mutations have been identified as causative for familiar Alzheimer’s Diseases (FAD), however, the molecular architectures of fibrils formed by most of these mutants remain underexplored. Here, the authors report the cryo-EM structures of Aβ fibrils formed by the Flemish (A21G) and Italian (E22K) mutants at resolutions of 3.1-4.0 Å and show that, despite structural differences, the oligomeric forms of both mutants are recognized by the natural neuronal Aβ receptor LilrB2.