Hydrogen Bond–Driven N-Terminal Amyloid β Mimetics Attenuate Neurotoxic Aggregation

Amyloid β (Aβ) aggregates are a neuropathological hallmark of Alzheimer’s disease (AD). Despite being a prime therapeutic target, past Aβ-targeted trials have primarily focused on its hydrophobic core, yielding unsatisfactory results. In this study, we aligned the structural features of Aβ₄₂ filaments and found that the hydrophobic core and C-terminal region show notable similarities, and the N-terminal region exhibits considerable disorder. Through residue substitution studies, we identified the His13-His14 motif at the disorder–order boundary as particularly effective in mitigating Aβ₄₂’s fibrillation pathway and neurotoxicity, alongside the Phe19-Phe20 hydrophobic core, presenting a promising target for therapeutic intervention. We then designed a series of peptide mimetics based on these Aβ features. Among them, peptide mimetic III, with the sequence of Phe-His-His, exhibited an assembly of antiparallel β-sheet structures primarily driven by hydrogen bonding, showcasing favorable rheological properties and biosafety. Interestingly, mimetic III predominantly patches the N-terminal region of Aβ₄₂ fibrils through hydrogen bond-dominated interactions, effectively modulating aggregation and neurotoxicity in a “like-interacts-with-like” manner. Furthermore, mimetic III eliminates the risk of Aβ₄₂ aggregating into neurotoxic intermediates, rescuing both human and mouse-derived neuronal cells from Aβ₄₂-induced toxicity. Our study demonstrated that peptide mimetics targeting the N-terminal region of Aβ₄₂ is a promising alternative for modulating amyloidosis-related neurotoxicity.