Function of Siglecs and sialic acids in neurodegeneration and neural regeneration
Sialic acids are enriched on the glycocalyx of neural and immune cells. They are terminal residues of carbohydrate chains attached to proteins and lipids. Microglial cells, as resident innate immune cells of the brain, and tissue macrophages, which invade the central nervous system in pathology, express sialic acid binding immunoglobulin-like lectin (Siglec) receptors that recogize the sialic acids of the cellular glycocalyx, thereby antagonzing activatory ITAM signalling pathways via their inhibitory ITIM signalling. Genetic variants of receptors (TREM2, CD33/SIGLEC-3) facilitating both, ITIM and ITAM signalling pathways, have been linked to Alzheimer’s disease. Our group is studying the impact of sialic acids as well as microglia and macrophage Siglec-receptors (CD33/SIGLEC-3, SIGLEC-11) on neural degeneration and regeneration.
Sialic acid based therapy approaches of neurodegenerative diseases
Sialic acid binding immunoglobulin-like lectin-11 (SIGLEC-11) is a primate-lineage specific receptor expressed on human tissue macrophages and microglia that binds to α2.8-linked oligosialic and polysialic acids (polySias). Soluble low molecular weight polySia with an average degree of polymerization 20 (polySia avDP20) interacts with SIGLEC-11 and consequently facilitates anti-inflammatory signalling on human macrophages. Activation of the SIGLEC-11 receptor by polySia avDP20 therefore leads to anti-inflammatory and anti-oxidative effects on human phagocytes. Our group is studying the therapeutic potential of low molecular weight polysialic acid as an anti-inflammatory molecule to protect neurons in in vitro and in vivo neurodegenerative model systems.
Methods and Techniques of the Neural Regeneration Group
Murine cell culture:
Primary murine cell culture of neurons, astrocytes and microglia; mouse embryonic stem derived microglia.
Human cell culture:
Human immortalized cell lines (THP1 etc.), microglia and macrophages derived from human induced pluripotent stem cells; neurons derived from human induced pluripotent stem cells.
Gene, protein and carbohydrate analysis:
Reverse transcription-PCR, Real-time PCR, and microarray transcriptome analysis; flow cytometry; fluorescence activated cell sorting (FACS); immunocytochemistry, fluorescence microscopy; confocal laser scanning microscopy; Western blot analysis, HPLC analysis.
Gene cloning and sequencing; gene transfection and transduction; lentiviral vectors and shRNA interference by lentiviral vectors; transgenic and knock-out mice.
Experimental animal models:
Experimental autoimmune encephalomyelitis (Multiple sclerosis animal model); neurodegeneration by repeated systemic application of lipopolysaccharides (Parkinson disease animal model).