Inflammatory neurodegeneration by sialic acid glycocalyx alterations

• Applicant: Dr. Bettina Linnartz-Gerlach
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317148800

Every cell surface is covered with a dense array of glycans, originally known as the glycocalyx, which mainly displays sialic acids at the terminal ends. Due to the exposed location, sialic acids are considered to play a crucial role in cell recognition and to mediate initial cellular interactions in physiological and pathological processes. Recently, we showed in vitro that murine and human neuronal structures having an altered glycocalyx with reduced sialic acid levels are recognized and phagocytosed by microglia/ macrophages in a complement receptor 3-dependent manner. In this proposal, we will investigate in vivo the impact of an altered glycocalyx using heterozygous GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) mice, a mouse model displaying reduced sialic acid levels. Heterozygous GNE(+/-) mice express about 32% less membrane-bound sialic acids in the brain. In these mice, we will study the relevance of the complement system for neurodegenerative and neuroinflammatory processes in the brain. First, we will investigate in detail the sialylation status of GNE(+/-) mice and whether they show signs of neurodegeneration and/or neuroinflammation. Second, we will analyze whether an inflammatory neurodegeneration could be prevented in GNE(+/-) mice by knock-out of complement component 3. Third, in a therapeutic approach we will restore normal sialylation levels in GNE(+/-) mice by the administration of a sialic acid containing milk oligosaccharide and we will study whether any inflammatory neurodegeneration will be prevented.Thus, data will elucidate in vivo the role of a reduced sialylation for neuroinflammatory and neurodegenerative processes. The long term aim is to develop novel therapy approaches for neuroinflammatory and neurodegenerative diseases.

• DFG Programme: Research Grants
• International Connection: Luxembourg
• Cooperation Partner: Lasse Sinkkonen, Ph.D.