Inflammatory neurodegeneration by sialic acid glycocalyx alterations
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
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. 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. Neuronal loss is a central event in neurodegenerative diseases and during aging. Furthermore, sialic acids can be easily removed during oxidative stress, a process occurring in the aging process, due to the exposed position and are shown to be decreased in the aged brain as well. Therefore, in this study the question was addressed whether reduced levels of sialic acids can lead to neuronal loss in the brain as proposed in the model based on in vitro data and whether aging plays a role using heterozygous GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) mice. These mice were tested as suitable in vivo model for reduced sialylation levels. Reduced Gne transcript levels resulted in hyposialylation of the cell surface in brain tissue. Especially, polysialylation and trisialylation were affected. Thus, GNE+/- mice are a suitable model for reduced brain sialylation. Moreover, accelerated neuronal loss was observed in the hippocampus as well as in the substantia nigra of GNE+/- mice compared to wildtype littermates that was preceded by synapse loss. However, GNE+/- mice showed no classical signs of a strong pro-inflammatory reaction indicating an innate homeostatic immune process. In vitro an altered sialylation status led to a complement-receptor 3-mediated removal of neuronal structures by microglia/macrophages. To investigate the relevance of the complement system for the neurodegenerative process in the brain, GNE+/- mice were crossbred with C3-deficient mice. C3- deficiency prevented the increased loss of synapses and the subsequent neuronal loss in GNE+/- mice. Thus, the complement system seems to be the driving force for neuronal loss caused by desialylation. As last step, a possible restoration effect of a sialic acid containing milk oligosaccaride application on sialic acid levels and neuronal loss should be investigated. Therefore, a model system for an easy and practicable application had to be established in the laboratory. First results of 6´-sialyllactose application in an animal model for hearing loss indicate a rescue effect on hair cell and sensory neuron loss. In summary in this project, mechanisms that had been previously demonstrated in vitro were successfully transferred into an in vivo system demonstrating the impact of glycocalyx alterations on neuronal well- being. The sialic acids as key molecules on the glycocalyx prevent neuronal loss during aging.
Publications
- Low levels of sialic acids facilitates age-related neuronal loss in mice. 4th ImmunoSensationCluster Science Days, Bonn, Germany, November 7-8, 2016
Schuy C, Hansen JN, Gerard D, Sinkkonen L, Halle A, Horstkorte R, Neumann H, and Linnartz-Gerlach B
- Altered sialylation promotes age-dependent neuronal loss in a mouse model. Bonn Immunoscience Days 2017, Bonn, Germany, November 13-14, 2017
Schuy C, Gerard D, Aurelien G, Sinkkonen L, Gnanapragassam VS, Horstkorte R, Neumann H, and Linnartz-Gerlach B
- Low levels of sialic acids facilitate age-related neuronal loss in mice. “Winterschool: Immunology meets Genomics and Bioinformatics”, Obergurgl, Austria, January 3-7, 2017
Schuy C, Hansen JN, Gerard D, Sinkkonen L, Halle A, Horstkorte R, Neumann H, and Linnartz- Gerlach B
- Low levels of sialic acids induce early neurodegeneration in aging mice. Abstracts of 13th European meeting on Glial Cells in Health and Disease, Edinburgh, Scotland, July 8-11, 2017. Glia 65(S1):E177, T05-032C
Schuy C, Gerard D, Sinkkonen L, Hansen JN, Halle A, Gnanapragassam VS, Horstkorte R, Neumann H, and Linnartz-Gerlach B
- Altered sialylation promotes neuronal loss in aging mice. Microglia 2018, Heidelberg, Germany, March 18-21, 2018
Schuy C, Gerard D, Ginolhac A., Sinkkonen L, Horstkorte R, Neumann H, and Linnartz-Gerlach B
- Complement-mediated neuronal loss by sialic acid glycocalyx alterations. Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn
Klaus, Christine
- Sialic acid as Translator of Neuronal Well-being for Microglia in Aging. Cluster Science Day 2018, Bonn, Germany, November 05-06, 2018
Klaus C, Gerard D, Ginolhac A, Sinkkonen L, Hansen JN, Gnanapragassam VS, Horstkorte R, Neumann H, and Linnartz-Gerlach B
- (2020) Reduced sialylation triggers homeostatic synapse and neuronal loss in middle-aged mice. Neurobiol Aging 88:91-107
Klaus C, Hansen JN, Ginolhac A, Gérard D, Gnanapragassam V, Horstkorte R, Rossdam C, Buettner FFR, Sauter T, Sinkkonen L, Neumann H, and Linnartz-Gerlach B
(See online at https://doi.org/10.1016/j.neurobiolaging.2020.01.008) - Effect of reduced sialylation on sensory neuronal inflammation and degeneration. 9th DGfI Translational Immunology School 2020, Potsdam, Germany, March 19-21, 2020
Assale TA, Klaus C, Linnartz-Gerlach B, and Neumann H
