Microglia Activation and Neurodegeneration in Multiple Sclerosis

Multiple sclerosis is a chronic inflammatory demyelinating disease leading to focal and diffuse neurodegeneration in the brain and spinal cord. Recent data suggest that the inflammatory process is associated with chronic microglia activation and oxidative stress in early disease stages, and that neurodegeneration in the progressive stage of the disease is amplified by additional pathogentic mechanisms related to brain aging and accumulation of lesion burden. While the early inflammatory stage of the disease is at least partly reflected in experimental models of autoimmune encephalomyelitis, tissue injury and neurodegeneration in the progressive stage have so far not been reproduced in the models. Our project is based on the hypothesis that chronic microglia activation, which occurs in the normal human brain in the course of aging, is a major driving factor for neurodegeneration in late stages of the disease and that similar mechanisms are also involved in the propagation of neurodegeneration in classical neurodegenerative diseases, such as for instance Alzheimers disease. Aim of this project is to systematically analyze the phenotype and function of microglia during normal brain aging and in diseases such as multiple sclerosis and Alzheimers disease and to compare these activation patterns with those seen in current rodent models of these diseases using a set of new phenotypic microglia markers. We will use new mouse and rat models, which at least in part reflect microglia activation and brain iron accumulation seen in the aging human brain, to determine their effect on neurodegeneration and to analyze whether inflammation-induced neurodegeneration is amplified or chronically propagated by pre-activation of microglia in the central nervous system. Our study will be performed by detailed pathological analysis and by gene expression studies. The results of our project are expected to provide major new insights into the mechanisms of neurodegeneration in chronic human inflammatory and neurodegenerative diseases. They may provide new experimental models for the testing of therapies for patients with progressive multiple sclerosis and neurodegenerative diseases and may identify new therapeutic strategies.

Recent evidence suggests that neuro-inflammation plays a major role in the induction of tissue damage not only in classical inflammatory diseases, such as multiple sclerosis, but also in stroke or neurodegenerative diseases, such as Alzheimers disease. Microglia cells, the resident immune cells within the brain and spinal cord, play an important role in normal brain homeostasis, brain plasticity and in the propagation of neurodegeneration. Our project provides for the first time a detailed account of the phenotype and function of microglia in human inflammatory and neurodegenerative diseases, including multiple sclerosis, stroke, Alzheimers disease and septic encephalopathy in comparison with the patterns of microglia activation in respective experimental rodent disease models. We found that the basic features of microglia activation are similar between human and experimental diseases, but that brain diseases in humans in contrast to experimental diseases in rodents develop on the basis of pre-activated microglia, most likely related to aging, environmental factors and age related comorbidities. We then addressed the question, whether microglia pre-activation triggers chronic neurodegeneration in the currently most commonly used experimental model of autoimmune encephalomyelitis. For this purpose we induced neuro-inflammation in two experimental models, which show patterns of microglia activation, similar to those seen in multiple sclerosis or virus encephalitis by transfer of auto-reactive CD4+ T-lymphocytes. Such microglia activation promoted inflammation selectively in the affected brain regions, but did not promote chronic neurodegeneration nor did it exacerbate the inflammation associated demyelination of neurodegeneration. These findings support that CD4+ T-lymphocytes, the cells which mediate autoimmune encephalomyelitis, do not play a major role in the propagation of progressive neurodegeneration in multiple sclerosis, a view which is supported by recent data from our laboratory on the nature of the inflammatory response in the brain of patients with active disease.