The role of peripheral immune cells, such as T-cells, in Alzheimer’s disease (AD) continues to become increasingly clear, with several major recent studies establishing clear links between these cells and hallmark pathologies like amyloid plaques and tau tangles. For decades, studies have also suggested a connection between viral infections and AD risk, though the mechanisms behind this link remain unclear. Several researchers propose that viral infections in the periphery alter immune cells like T-cells, and that these changes affect how they respond to AD pathologies. Dr. Herz has studied this hypothesis for several years and plans to continue this research to identify specific changes in inflammatory signals caused by viral infections.
Dr. Herz’s previous work showed that viral infection in an amyloid mouse model increased several important inflammatory signaling molecules, or cytokines. While this increase was expected during a viral infection, her team also found that it was linked to more immune cells moving to and staying in the brain and its protective barriers, called the meninges. Several of the elevated cytokines are known to affect immune cell function and movement, including IL-18 and CCR5. With these potential mediators identified, Dr. Herz now plans to confirm their role in increasing peripheral immune cell migration and subsequent worsening of Alzheimer’s disease (AD) pathology. She also hypothesizes that these anti-viral cytokines influence neurons in the hippocampus, a region of the brain heavily impacted by AD and responsible for memory formation, thus altering disease progression.
She proposes two experimental aims to continue her investigation. In the first, she will virally infect a mouse model of aggressive amyloid deposition and then assess changes in hippocampal neurons, T-cell infiltration, and cell-specific inflammatory responses using advanced spatial transcriptomic techniques. These methods enable Dr. Herz to identify how the location of different cells influences others. She is particularly interested in understanding how infiltrating T-cells affect neurons in the hippocampus. She will also examine changes in the brain’s blood vessels and meninges to see if the viral infection impacts their ability to serve as protective barriers. Additionally, she will selectively neutralize specific cytokines and deplete T-cells to assess their relative contributions to the observed changes. Essentially, this aim intends to define how T-cells and antiviral cytokines alter the hippocampal microenvironment. In the second aim, she will conduct a similar experiment with infected amyloid mice but will focus on the effects on amyloid pathology and cognitive function. She will employ similar neutralizations of IL-18 and CCR5 to determine their roles in worsening pathology and cognitive deficits. While the first aim investigates changes in the hippocampal microenvironment, the second focuses on how these cytokines contribute to Alzheimer’s disease-specific pathologies.
This project aims to define a mechanistic connection between AD risk and viral infections through increasingly significant mechanisms involved in peripheral immunity. In doing so, potential therapeutic targets may be identified at various points along this mechanism, enabling preventative strategies for AD.
