Antimicrobial Peptides as Cross-Seeding Modulators at the Neurodegenerative-Infectious Interface

Antimicrobial peptides (AMPs), traditionally regarded as innate immune effectors, are increasingly recognized for their structural and functional convergence with pathogenic amyloids. Recent studies-including our own-reveal that AMPs not only exhibit antimicrobial activity but also modulate amyloid aggregation by accelerating, delaying, or redirecting fibril growth, acting at the nexus of protein misfolding, inflammation, and host defense. In this account, we highlight the emerging role of AMPs as cross-seeding modulators that can inhibit or promote amyloid fibrillization depending on structural context. We summarize mechanistic insights into how β-sheet-rich AMPs engage amyloidogenic targets via structural compatibility, directional seeding asymmetry, and surface-mediated catalysis. We also explore how AMP-amyloid cross-seeding contributes to a bidirectional pathogen-amyloid feedback loop, linking microbial infections to chronic inflammation and neurodegeneration. Building on these molecular foundations, we present recent design advances in engineering AMP-derived inhibitors with enhanced amyloid specificity, proteolytic stability, and translational potential. These dual-function peptides-capable of suppressing amyloid aggregation and modulating immune responses-offer a unique therapeutic strategy for diseases such as Alzheimer's, type 2 diabetes, and systemic amyloidosis. We conclude by outlining current challenges and future directions for data-driven design, delivery optimization, and clinical development of multifunctional AMPs as next-generation therapeutics.