Dr. Eimer is pursuing a hypothesis pioneered by the late Dr. Rob Moir in collaboration with Dr. Rudy Tanzi that challenges the dominant theory that the amyloid beta peptide is simply a toxic byproduct of the normal processing of the amyloid precursor protein. Their counter theory suggests that amyloid beta has been conserved across 400 million years of evolution because it functions as an antimicrobial peptide in the brain. Antimicrobial peptides are small proteins that act as agents of the innate immune system to react quickly to the presence of pathogenic microbes. Early work from Drs. Moir and Tanzi showed that amyloid plaques form quickly around microbial pathogens (bacteria, fungus, viruses) when tested in neuronal cell cultures, effectively isolating the pathogen and protecting neighboring cells from potential damage. Additionally, mice engineered to produce high levels of amyloid beta survive better than control mice after being infected with several types of bacteria and viruses, while mice engineered to produce lower levels of amyloid beta had worse survival. Due to the strength of their data, CureAlz supported this work for years when the rest of the field would neither publish nor fund it due to its intellectual nonconformity. Now that the vital role of the immune system in AD is a mainstream concept and the team’s data has continued to strengthen and has been replicated, their Antimicrobial Peptide Hypothesis is a key part of the conversation about the role of infection in disease onset and progression.
Previous research in the Eimer lab explored how amyloid beta accumulates into the large aggregates that encase and segregate microbes and how pre-plaque forms of amyloid beta directly signal immune cells to trigger other immune-related responses. Their findings demonstrated that amyloid beta, like other antimicrobial peptides, combats microbes both directly and indirectly. Building on this foundation, the Eimer lab shifted its focus to the other hallmark of Alzheimer’s disease (AD), tau, to investigate whether it also possesses antimicrobial properties. Their initial finding showed that tau did exhibit antiviral activity against the herpes simplex virus (HSV1). Over the last year, the team has investigated whether tau functions as a true antimicrobial peptide. Overall, their data support the hypothesis that both amyloid beta and tau are important members of the brain’s first-line innate immune system and suggest that pathogens—infections—might be involved in the etiology of AD.
Dr. Eimer is pursuing three aims in this follow-on project. In the first aim, they are investigating how amyloid beta influences the immune response to pathogens. These experiments begin in cell models, where the Eimer lab is measuring gene expression changes in neurons and microglia (the brain’s immune cells) and the levels of inflammatory cytokines after introducing the virus HSV1. To strengthen the case for translational relevance, they are then conducting similar experiments in amyloid and tau mouse models. In the second aim, they are exploring how amyloid beta binds to infected cells and triggers their destruction. They predict that this binding activates autophagy—a process that degrades cellular components and leads to cell death. In the third aim, they are continuing their initial studies on the potential role of tau as an antimicrobial protein in cell cultures.
At the close of the first year of funding, the team has made notable progress, particularly in Aim 3. They discovered that tau, like amyloid beta, acts as an antimicrobial peptide against HSV1 infections in cell models. By binding to and aggregating the virus, tau not only protected cells from infection but also slowed its spread to neighboring cells. Building on these findings, the team is now investigating tau’s antimicrobial efficacy against a broader range of pathogens, including bacteria, fungi, and parasites.
In the next year of funding, the team plans to pivot back to Aims 1 and 2 and resume experiments investigating amyloid beta’s role in the immune response, including RNA sequencing of amyloid beta-expressing cultures infected with HSV1 and other herpes viruses. These analyses will provide critical insights into the pathways involved in amyloid beta’s immune targeting of infected cells and its modulation of immune responses through cell surface binding partners under infectious conditions.
