APOE Genotype Difference in the Biphasic Modulation of Amyloid-β Aggregation by Direct Binding and Lowering the Nucleation Barrier.

ABSTRACT: Amyloid-β (Aβ) aggregation is a hallmark of Alzheimer's disease (AD), while the apoE4 isoform (C112R) represents the strongest genetic risk factor. We combined binding-site mapping and discrete molecular dynamics (DMD) simulations to elucidate isoform-specific apoE-Aβ interactions. Computational peptide-array analysis identified Aβ-binding hotspots in the apoE4 N-terminal domain (NTD) around R112, conferring greater Aβ-binding propensity than apoE3. DMD simulations showed that apoE4 NTD is less stable and more solvent-exposed, resulting in stronger Aβ binding, especially near the mutation site. Upon binding apoE NTDs, Aβ exhibited an increased β-sheet content, suggesting a lowered fibril nucleation barrier. Incorporating these insights into a recently established thermodynamic-kinetic fram

SUBMITTER: Song Z 

PROVIDER: S-EPMC12709511 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature