Neurodegeneration in Multiple Sclerosis: The role of oxidative damage

Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to demyelination and neurodegeneration. The mechanisms of tissue injury are currently poorly defined in MS patients and experimental models reflect this process only to a limited degree. We have recently found that mitochondrial injury, most likely induced by oxidative damage, plays a major role in neurodegeneration in MS patients. The hypothesis, which forms the basis of this application, is that in early stages of multiple sclerosis inflammation drives neurodegeneration through oxidative burst in microglia and macrophages. However, in the progressive stage of the disease, where inflammation declines oxidative burst is amplified by the liberation of toxic Fe++, due to age related iron accumulation in the aging brain. Our previous data further suggest that neurodegeneration through inflammation and oxidative burst in part also occurs in experimental models of MS, but that the chronic amplification of oxidative burst by iron is not reflected in the respective models. We, thus, intend to systematically analyze the presence of oxidized DNA and oxidized lipids in a large archival sample of MS patients, covering all stages of the disease and including all the different types of MS lesions. This will be compared to oxidative damage in control brains without lesions as well as in other inflammatory and neurodegenerative diseases of the central nervous system. In the second step we will investigate the expression of molecules, involved in oxidative burst, in the lesions and their relation to oxidative damage. In addition we will analyze in detail the dynamics of iron accumulation in the human brain or MS patients and controls in relation to oxidative damage. Finally we will apply the same technology to determine oxidative damage, oxidative burst and iron accumulation in different experimental models of brain inflammation, induced by Class I or Class II MHC restricted T-cells, as well as in demyelinating and destructive lesions triggered by innate immune mechanisms or in chronic demyelinating lesions mediated by T-cells and demyelinating auto-antibodies. We expect that this study will provide important insights into the mechanisms of demyelination and tissue injury in MS patients, which will serve the basis for the development of new neuroprotective treatments.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, which leads to focal lesions with demyelination and neurodegeneration in the brain and spinal cord. In most patients multiple sclerosis starts as a relapsing and remitting disease, which converts into a progressive neurological course 10 to 15 years after its onset. Some patients miss the relapsing stage of the disease and start with a course of uninterrupted progression. A major factor associated with the conversion of relapsing disease into the progressive phase is the age of the patient. Currently potent anti-inflammatory treatments are available, which reduce disease relapses in the early phase of the disease, but no treatment can be offered for patients, who have entered the progressive phase. An essential requirement for the development of new treatment strategies is to understand the pathophysiological mechanisms, which lead to demyelination and neurodegeneration in multiple sclerosis patients. Central aim of our project was to define what drives disease and tissue injury in patients with progressive multiple sclerosis. This was conducted with a combination of modern neuropathological techniques with gene expression studies in micro-dissected lesions and by the analysis of experimental disease models. Our studies show that there is a unique disease signature of inflammatory demyelination, which distinguishes multiple sclerosis from any other brain disease. Demyelination and neurodegeneration in the brain of multiple sclerosis patients occur on the background of massive oxidative injury and mitochondrial damage, resulting in oligodendrocyte destruction and demyelination as well as in energy deficiency and ionic imbalance of neurons. Inflammation and microglia activation are major factors driving oxidative injury in early disease stages. However, when patients enter the progressive stage, oxidative injury is amplified by additional mechanisms, which are related to brain aging and the accumulation of lesion burden. These factors include chronic microglia activation as a result of aging and progressive neurodegeneration and the age related iron accumulation within the human brain. Based in part on the results of this project new neuroprotective treatment strategies are currently tested in patients with progressive multiple sclerosis, aimed to protect the brain against oxidative stress, to prevent or ameliorate mitochondrial dysfunction and to inhibit the consequence of energy deficiency on neuronal function and survival. Although current experimental disease models are suitable to study aspects of brain inflammation and to test anti-inflammatory therapies for multiple sclerosis patients, the results of our project show that they reflect chronic oxidative and mitochondrial injury, as typically seen in the brain of patients with progressive multiple sclerosis, only to a very limited degree. Thus, until better models are available, screening of potential therapeutic strategies for patients with progressive multiple sclerosis has to be done in clinical trials.