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

2023

Previous findings from our lab identified amyloid beta as an antimicrobial peptide. We demonstrated that amyloid beta was capable of protecting cells, worms and mice against infections from bacteria, yeast and viruses. In the first year of this study, we have greatly expanded on our previous research. Examining tau, the other major peptide involved in Alzheimer’s disease, we found antimicrobial properties against herpes simplex virus 1 (HSV1) infection in human cell models. Tau was able to bind to HSV1, prevent infection of cells and slow down the expansion of HSV1 from infected cells. Additionally, the binding activity of tau also was improved when it was phosphorylated, a form of tau often found in abundance in Alzheimer’s disease patients. Interestingly, we also observed a more robust, tau-based immune response when there was increased amyloid beta, suggesting that amyloid beta’s and tau’s immune responses to herpes simplex virus 1 are interconnected. These data provide support for the growing hypothesis that amyloid beta and tau are important members of the brain’s innate immune system, and could be pivotal elements in an immune-impacted pathology of AD.

2021

Alzheimer’s disease (AD) has long been associated with two proteins: amyloid beta and tau. These are most often observed in the AD brain as amyloid plaques and tau tangles. As such, these proteins have been the primary focus of research groups and pharmaceutical companies searching for a treatment. This line of reasoning is firmly grounded in the idea that the amyloid beta and tau observed in diseased brains are a mistake of the body, resulting in the progression of the disease that leads to neuron loss, memory failure and eventual death. Unfortunately, recent drug trials have failed to halt or slow down AD progression despite successfully removing amyloid beta. Our recent research proposes an alternative: the amyloid beta peptide’s previously perceived abnormal properties are consistent with those of antimicrobial peptides (AMPs), and that amyloid beta is an important player in the immune system. AMPs are a family of peptides and proteins that serve as the first line of defense against bacteria, yeast, fungi and viruses. Our findings revealed that aggregation and generation of amyloid are important parts of amyloid beta’s role in immunity, mediating the capture and neutralization of pathogens in the 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. These findings suggested that an immune response involving amyloid beta may be important to AD pathology.

Our proposal will characterize amyloid beta’s role as an AMP by examining its impact at physiological levels on immune system responses in both mouse and a three-dimensional human neural progenitor cell culture system. We will examine whether amyloid beta contributes to neuron death by selectively targeting neurons that already are infected, or whether amyloid beta acts as a signal for microglia to engulf the infected cell. Finally, we will expand our antimicrobial hypothesis by demonstrating that tau is also an AMP. Our preliminary data demonstrate that tau already exhibits some potent anti-bacterial abilities. The field of AD is shifting away from treating amyloid beta as a target for removal, and we think our proposed study solidifies the importance of immune responses and inflammation in AD etiology. We expect these findings to provide important information for current and future AD prevention and treatment therapies.