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

The last decade of research on Alzheimer’s disease (AD) has seen the development of various anti-amyloid beta therapies (with limited efficacy) but also a significant renewed interest in the roles that microbes may play. While many different pathogens have been identified in higher levels in AD patients’ brains, no microbe has definitively been causative of the disease. To answer this discrepancy, our team proposes that amyloid beta and tau are antimicrobial peptides (AMPs), and these two important AD-related proteins are integral parts of the brain’s innate immune system. AMPs serve as a family of peptides and proteins that act as the first line of defense against pathogenic microorganisms. Previous support from Cure Alzheimer’s Fund helped us identify amyloid beta’s ability to aggregate bacteria and viruses, protecting the host from infection. Our most recent discoveries revealed that amyloid beta influences pathways affecting inflammation and cell death. Significantly, we also found evidence that tau is also an AMP against viruses. These findings suggest that an immune response involving both amyloid beta and tau may be important in AD pathology. Our proposal will build upon our most recent findings by utilizing a complex 3-dimensional human neuronal cell culture system and mouse model to dissect the mechanisms behind how amyloid beta and tau function in the immune system of the brain. We will examine how amyloid beta can influence inflammatory and cell death pathways during infection. We will decipher amyloid beta’s role in autophagy during viral infections. Finally, we will expand our understanding of how tau functions as an AMP against viral and bacterial microbes. We believe our proposed study is an essential key to understanding amyloid beta, tau, inflammation and AD. Bridging the various fields of study under a unified understanding of disease pathology is necessary for the development of targeted and effective treatments.