Abstract
A considerable body of data suggests the beta-amyloid peptide (Abeta) plays a key role in Alzheimer’s disease (AD) pathology. The physiological role for Abeta has been unclear. We recently showed that synthetic Abeta has potent in vitro antimicrobial activity against CNS pathogens. We have since generated in vivo evidence showing that Aβ protects against fungal and bacterial pathogens in transgenic mouse, Drosophila, C. elegans, and culture cell infection models, doubling host survival in some cases. Consistent with a protective role for Aβ in vivo, APP-null mice with low Aβ expression also show attenuated infection resistance. Oligomerization of Abeta is key for the protective antimicrobial actions of the peptide and mediates the agglutination and eventual entrapment of microbes in beta-amyloid deposits. The emergence of role for Abeta as an antimicrobial peptide (AMP) and recent identification of innate immune genes as AD risk factors has lead us to propose a new disease model we call the “Antimicrobial Protection Hypothesis” of Alzheimer’s disease. Here we present data on how Abeta activities mediate the peptides AMP actions against fungal, bacterial and viral pathogens. We describe how our new model provides a framework for understanding Abeta activities, including host cell cytotoxicity, metal binding and oxygen radical generation, carbohydrate binding, and immune modulatory activities.