Tau and Amyloid Beta are Innate Immune Antimicrobial Peptides in the Brain

Alzheimer’s disease therapeutic trials recently have been dominated with targeting the prevention or removal of the amyloid beta peptide. This has been predicated on the hypothesis that amyloid beta is a useless byproduct of metabolism that abnormally aggregates, driving AD pathology. Our recent research demonstrated that the amyloid beta peptide’s previously perceived abnormal properties are indicative of antimicrobial peptides. AMPs are a family of important peptides and proteins that serve as the first line of defense against bacteria, yeast, fungi and viruses. Our findings revealed aggregation and generation of amyloid are important parts of amyloid beta’s role in immunity, mediating the capture and neutralization of pathogens in brain. In our experiments, genetically modified cells, nematode worms, fruit flies and AD mice expressing human amyloid beta were protected from infection by amyloid-mediated entrapment of the invading pathogens. Our findings suggest that an immune response to pathogens may be initiating or accelerating AD pathology. Our planned studies will characterize amyloid beta’s role as an AMP by examining its function at physiological levels in both mouse and a three-dimensional human neural progenitor cell culture system. In addition, we will explore amyloid beta’s destructive properties, selectively targeting neurons that already are infected. Finally, we will expand our antimicrobial hypothesis by demonstrating that tau, the second important peptide in AD, is also an AMP. Our preliminary data already suggests tau is a potent antibacterial. We think our proposed study will contribute significantly to the shifting of hypotheses surrounding AD etiology and pathology toward immune responses and inflammation. These findings will provide important information for current and future AD prevention and treatment therapies.