019 – Cortical microglia in progressive MS acquire a unique phenotype in response to chronic meningeal inflammation

17 Lug 2019
12:35 - 12:45
IMMUNOLOGY, POSTER

019 – Cortical microglia in progressive MS acquire a unique phenotype in response to chronic meningeal inflammation

Lynn van Olst (1) – C Rodriguez Mogeda (1) – S Kilian (2) – I Michailidou (3) – C Picon Munoz (4) – E Drost (1) – S van der Pol (1) – S Jonk (1) – F Baas (3) – G Schenk (2) – J Geurts (2) – J van Horssen (1) – HE de Vries (1) – R Reynolds (4) – ME Witte (1)
Amsterdam UMC, Molecular Cell Biology and Immunology, Amsterdam, Netherlands (1) – Amsterdam UMC, Anatomy & Neurosciences, Amsterdam, Netherlands (2) – Leiden University Medical Center, Clinical Genetics, Leiden, Netherlands (3) – Imperial College London, Division of Brain Sciences, Department of Medicine, London, United Kingdom (4)


Cortical neurodegeneration, which encompasses the major loss of synapses, dendrites and neuronal cell bodies, is widely accepted as the main contributor to clinical disability in progressive MS patients. However, remarkably little is known about the mechanisms underlying this cortical neuronal pathology. It is currently unknown whether cortical microglia actively contribute to neurodegeneration in MS, protect neurons from further damage or switch between both phenotypes. One of the main reasons for this gap in our knowledge is the absence of a proper animal model for MS-related cortical pathology. Here, we extensively characterized cortical microglia in a large cohort of human post-mortem brain tissue to show that in progressive MS, cortical microglia adapt a more ramified morphology, lose expression of homeostatic markers and upregulate proteins related to activation. This altered microglial phenotype, which is different from other age-related neurodegenerative diseases, associates with local inflammation of the meninges and correlates with the extent of neuronal loss. Remarkably, microglia appear to physically interact with damaged neurons in MS cortex, which was previously described as a neuroprotective act. Secondly, we performed similar experiments in a novel animal model for cortical MS pathology. In this model, we induce chronic inflammation of the meninges overlying the rat cortex, resulting in cortical demyelination and neuronal loss. Similar to progressive MS, we observe increased morphological complexity of cortical microglia, upregulation of microglial activation markers and a close interaction with neuronal cell bodies. Taken together, we conclude that chronic meningeal inflammation induces a unique cortical microglial phenotype in progressive MS patients. Whether these microglia contribute or try to salvage ongoing neurodegeneration warrants further study.