Biofilm Biology to Brain Health: Harnessing Microbial Wisdom to Uncover Amyloid Dissociating Bifunctional Nano Chaperones for Alzheimer’s Therapeutics

Microbial infections have long been implicated in the gut-brain link to Alzheimer's disease (AD). These infections may influence AD development either directly, through brain invasion, or indirectly via bacterial metabolites crossing the blood-brain-barrier (BBB) or interacting with the enteric nervous system (ENS). Such findings have inspired clinicians to repurpose antimicrobial drugs for AD, yielding promising results. However, the sole bacterial link to AD may be insufficiently understood. Bacterial amyloid presence in biofilms is well-documented, with certain bacterial proteins exacerbating amyloid formation while others inhibit it. For instance, Curli-specific gene protein C (CsgC) in E. coli suppresses curli amyloid formation. This review investigates the possibility of human CsgC-like proteins, identifying beta-2 microglobulin (β2M) and E3 ubiquitin ligases (E3s) as potential analogs that may influence amyloid degradation. We propose that nanoparticles (NPs) could serve as platforms to anchor these proteins, forming Amyloid Dissociating Bifunctional NanoChaperones (ADBiNaCs) with enhanced antiamyloidogenic activity. This innovative approach holds promise for novel AD treatment strategies, meriting further investigation into the role of bacterial and human amyloid-modulating proteins in AD pathology.