Genetic and experimental studies have strongly linked innate immune cells and neuroinflammation to Alzheimer’s disease. Microglia—one of the brain’s resident immune cell types—monitor the brain’s environment and respond to pathogens or injuries. They can shift between different functional states, including an inflammatory mode (where they release chemical signals called cytokines) and a phagocytic mode (where they engulf and digest amyloid, damaged synapses, and debris). Their ability to dynamically move between these states and return to the resting homeostatic state is crucial for a healthy brain. Astrocytes—another innate immune cell type—can respond similarly, and recent work suggests that their reaction may depend in part on crosstalk with microglia. Determining when and how glial cell (microglia and astrocytes) activation escalates into chronic neuroinflammation and, more importantly, how to intervene is a major goal for the Alzheimer’s research community. By understanding these processes, scientists hope to develop treatments that could modify these immune cell types to benefit people living with Alzheimer’s disease.
Dr. Weiner is an expert in the interplay between immunology and brain disease. He has a long-standing interest in using immunotherapy to treat neurological conditions—most notably multiple sclerosis, but also ALS, and Alzheimer’s disease. In this proposal, he draws from his extensive experience studying the signals that control microglial state changes and the recently recognized ability of peripheral adaptive immune cells (T cells) to enter and act in the brain. The Weiner lab is pursuing a very novel strategy to control microglia by activating a T-cell response that recognizes proteins unique to microglia. They propose that these trained T cells can infiltrate the brain and specifically home in on microglia to impact their functions in a way that prevents or reverses Alzheimer’s-related pathologies. Their preliminary work supports this approach. Immunizing mice with candidate microglia proteins activated T cells and further experiments showed that injecting amyloid model mice (APP/PS1) with one of these proteins—FCRLS peptide #15—shifted microglia toward a homeostatic state while lowering amyloid levels in the brain.
The Weiner lab proposed three specific aims. In the first aim, they are investigating how T cells influence microglia and how these changes impact Alzheimer’s disease in experimental models. To do this, they are immunizing mice from two amyloid models (APP/PS1 and 5xFAD) and one tau model (PS19) with FCRLS peptide #15. They are measuring how this treatment affects astrocyte and microglial activity and brain levels of toxic amyloid and tau. Additionally, behavioral tests are being performed to determine whether changes in Alzheimer’s-related pathology lead to measurable changes in the mice’s cognition and memory. In the second aim they are identifying the type of T cells mediating these protective effects in the brain. Based on their screening methods, they predict that CD4 T cells are involved, but CD4 T cells have multiple subtypes with different functions, so they are studying which ones enter the brain and interact with microglia after immunization. Similar to experiments outlined in Aim 1, amyloid model and tau model mice are being immunized with CD4 T cells, and the same outcomes—astrocyte and microglial activity, toxic amyloid and tau levels, and cognitive function—are being evaluated. To pinpoint which CD4 T cell subtypes contribute to microglia changes after immunization, they are using antibodies to selectively block the function of different subtypes, including Th1, Th2, Th17, and Treg cells. Finally, in the third aim, they are exploring if immunizing mice with proteins only made by activated microglia could trigger an even more robust reduction in pathology. The team has already identified several candidates unique to activated microglia and will follow the methods and outcomes in Aim 1 after immunization. In this last aim, they will also explore the potential role of the CD8 T cell class.
In the first year of funding, Dr. Weiner’s team laid substantial groundwork for the successful completion of the proposed aims. The mouse colonies for the required studies have been established, and the team is now waiting for the mice to reach the appropriate age. Initial sets of APP/PS1 mice have been immunized with peptide #15, and single-cell sequencing is underway in microglia and astrocytes collected from these mice. Immunizations in the other two mouse models are also in progress and will be completed in the second year. Work on Aims 2 & 3 is planned for the second year and requires completion of Aim 1.
