Role of glial-neuronal metabolic communication in autoimmune neuroinflammation

• Applicant: Dr. Marina Herwerth
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 444138499

The metabolic communication between astrocytes and neurons is crucial for neuronal maintenance and survival. Astrocytes supply neurons with energy metabolites, inactivate toxic waste, ensure a constant water equilibrium between extra- and intracellular compartments and exert mediators that modulate signaling pathways in neuroinflammatory environment. Models of astrocytopathy for exploration of neuronal fate in neuroinflammation are lacking. However, Neuromyelitis optica (NMO) is one type of neuroinflammatory disorders that represents a clear astrocytopathy disease. In NMO, patients suffer from severe relapses with poor recovery, resulting in accumulating neurological deficits that are likely due to neuronal damage. Most NMO patients carry a serum autoantibody against Aquaporin-4 (AQP4-Ab), an astrocytic water channel that in the central nervous system (CNS) is expressed in astrocytes. After entry to the CNS, AQP4-Ab damage astrocytes via complement, resulting in astrocyte necrosis. Finally, NMO lesions show demyelination and axon injury. However, how the pathology in NMO spreads beyond initial astrocytopathy leading to neuronal injury and neurodegeneration remains unclear. The involvement of all cell types emphasizes how tightly glia and neurons communicate in the CNS, suggesting that cell death of one cell type has an impact on the others, particularly in the context of neuroinflammation. Here, we propose a research project to investigate glial-neuronal metabolic communication and its possible alterations during neuroinflammation in a mouse model of NMO. Combining innovative biological approaches with cutting-edge methodological tools, we want to investigate the impact of AQP4-Ab mediated neuroinflammation on glial-neuronal communication both on a short- and long-term scale. Hereby, we will address key questions about the metabolic mechanisms underlying neurodegeneration under autoimmune neuroinflammatory conditions. Thus, this project will gain insights into astrocytopathy driven neuronal damage that have a great potential to reveal paradigmatic pathomechanisms in neuroinflammation and thus provide a basis for new therapeutic strategies for various neuroinflammatory diseases.

• DFG Programme: WBP Fellowship
• International Connection: Switzerland
• Host: Professor Dr. Bruno Weber