The inhibition of the Aβ-ASC interaction site suppresses β-amyloid aggregation and cytotoxicity.

Background and aims: The deposition of β-amyloid (Aβ) in the cerebral cortex and hippocampus is a key pathological hallmark of Alzheimer's disease (AD). Previous studies have shown that ASC specks released by activated microglia can bind to Aβ and promote its aggregation, thereby accelerating AD progression. However, the specific mechanisms underlying this interaction remain poorly understood. This study aims to identify the interaction sites between ASC and Aβ, design a vaccine targeting these sites, and evaluate its immunogenicity and therapeutic efficacy. Methods: The interaction regions between ASC and Aβ were identified using pull-down and ELISA assays. Four types of nanoparticle carriers were purified using a prokaryotic expression system, and two peptides targeting the interaction sites were synthesized Results: Pull-down and ELISA results demonstrated that the C-terminal region of Aβ, particularly residues 29-42, and the pyrin domain (PYD) of ASC are key regions involved in binding. Eight nanoparticle vaccines carrying Aβ C-terminal epitopes were successfully prepared. Among them, the Ferritin-based Aβ vaccine induced a potent immune response targeting the Aβ-ASC interaction site without activating Aβ-specific T-cell responses. Discussion: Our findings indicate that the interaction site between ASC and Aβ is located within amino acids 29-42 of Aβ. Vaccines designed based on this site, Ferritin-Aβ29-35-3copy and Ferritin-Aβ36-42-3copy, effectively induced antibody production. The resulting antibodies suppressed Aβ aggregation and the neurotoxicity of Aβ oligomers. These data suggest that the Aβ-ASC interaction site may represent a potential target for AD therapy.