Immunoregulatory control of microglial cells in neurodegenerative and neuroinflammatory diseases

• Applicants: Dr. Deborah Kronenberg-Versteeg; Dr. Andreas Wild
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568748794

Neurodegenerative or neuroinflammatory diseases such as Alzheimer’s disease (AD) or Multiple Sclerosis (MS), respectively, are grave and debilitating disorders, whose incidences rise steadily due to the general aging of society. Apolipoprotein E (APOE) is the leading genetic risk factor for late-onset Alzheimer’s disease (AD), whereby the APOE4 allele confers the greatest risk of disease and APOE2 is associated with a reduced risk when compared with the most common APOE3 allele. Recent research indicates that APOE4 genotype results in compromised antigen presentation in microglia, which may be critical for mounting the appropriate functional responses to the developing disease pathology and could provide a link to neuroinflammatory processes. Work from our own laboratories has shown that CD83 is a key regulatory molecule with immunomodulatory capacities in neuroinflammatory conditions. Human single-cell microglial gene expression data from ROSMAP showed an APOE allele-dependent differential gene expression of CD83, a finding we were able to confirm in iPSC-derived microglia (iMG). Since CD83 also stabilizes MHC-II on antigen-presenting cells, we propose a feedback loop between APOE4, CD83 and HLA-DR that critically shapes microglial activation in response to the developing pathology and subsequently the severity of AD and MS. We will investigate the impact of APOE allele on the expression kinetics of CD83 and HLA in iMG in response to inflammatory stimuli as well as amyloid beta oligomers. Furthermore, we plan to assess the interplay between APOE isoforms and CD83 in organotypic murine brain slices seeded with human iMG on amyloid deposition and spread of pathology. Finally, we will test the effect of CD83-deletion in an in vivo model for AD as well as the effect of APOE4 in an MS model system. In addition, our preliminary data suggest that the soluble isoform (sCD83) has profound immunomodulatory and disease-modifying effects in a mouse model of autoimmune inflammatory disease. In the present project, we aim to elucidate the effect of sCD83 treatment on microglial function as well as the development of neuroinflammatory and amyloid pathology to assess its efficacy as a potential new therapeutic avenue for MS and AD, respectively. We will also investigate whether sCD83 in the CSF of patients can be used as a prognostic marker for these diseases. Overall, this project will contribute to our understanding of the immunoregulatory function of the APOE-CD83-HLA signalling axis and provide insights into a potential therapeutic intervention of sCD83 in neurodegenerative and neuroinflammatory diseases.

• DFG Programme: Research Grants