| Innate immunity in neurodegenerative diseases | | Microglial cells, the resident macrophages of the central nervous system, serve as the key cells in neuroinflammation. They are constitutively active to sense any environmental changes. Microglial cells are derived from the hemangioblastic mesoderm during the embryonic stage and a certain part of them are continuously replenished by bone marrow-derived myeloid cells in adulthood. Interestingly, this replenishment will be strongly enhanced in diseases, such as Alzheimer?s disease (AD), Parkinson?s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Our research group is very interested in the function of microglial cells in those neurodegenerative diseases. In AD, a two-edged sword effect is suggested by current research performed by us and others: Whereas, the clearance of Aβ deposits via phagocytosis is considered to be beneficial (Liu et al., Brain, 2005), the proinflammatory activation and release of neurotoxic products are assumed to be detrimental (Fassbender et al., FASEB J, 2000, 2004). We are also investigating mechanisms through which microglial cells perform their pathological relevant functions, e.g. through recently discovered innate immune receptors and matrix metalloproteases. CD14 and Toll-like receptors are responsible for the recognition of highly conserved pathogen-associated structural motifs on microorganisms and currently are also observed to react to endogenous ligands in the brain, e.g. to amyloid peptid (Aβ), the key molecule in AD. Furthermore, we observed that CD14 both, enhances Aβ fibrils-induced microglial proinflammatory activation and phagocytosis. (Fassbender et al. FASEB J, 2004 and Liu et al., Brain, 2005). Interestingly, our screening of CD14 and most of the TLRs showed a common pattern of upregulation of CD14 and TLR2 in all neurodegenerative diseases studied, i.e. AD (Figure 1, Letiembre et al, Neurobiol Aging, 2007), PD and ALS. The functional relevance of those altered receptor expression in AD and ALS is under investigation (Liu et al., JBC 2008). 
Fig. 1: CD14, TLR2 and Aβ plaques in AD human brain sections. CD14 (left picture, red), TLR2 (right picture, red) and Aβ (left: brown, right: green) positive immunostaining are shown. Scale bar = 50µm. | | | Normal aging of the brain | | Increasing life expectancy in Western countries raises considerable health problems as normal aging is known as the most important risk factor for neurodegenerative disorders such as AD and PD. Actually, even physiological aging of the brain is associated with various morphological and functional alterations including cytoskeleton changes and neuronal atrophy with activation of microglial cells. A better knowledge of the brain aging processes, especially at the molecular level would help us to understand how normal aging can lead to neurodegeneration. Recently, we demonstrated that even physiological aging of the brain is associated with regulation of TLRs, most of them showing an up-regulation (Letiembre et al, Neuroscience, 2007). Why and how such innate immune receptors are regulated with age even in absence of disease is currently under investigation. | | | Statins and Alzheimer's disease | | Epidemiological studies revealed a strong protective effect of cholesterol lowering drugs, such as statins, on progression of AD. Furthermore, the number of people carrying both allels of ApoEe4, a cholesterol transport protein, is ten times higher in AD patients than in controls. In recent studies we studied the effects of lipid lowering drugs (HMG-CoA reductase inhibitor, statins) and we showed that simvastatin reduces the neuronal secretion of the Alzheimer amyloid peptide in vitro and in vivo (Faßbender et al, PNAS, 2002). Now, we further investigate the interaction between cholesterol and Aβ in animal models, and we translate these results in the clinical practice by large multicenter EU (Lipidiet) or BMBF (SimaMCI) projects. | | | Pathophysiology of Stroke | | In molecular and cellular biological studies, immuno-histochemical investigations and in vivo-techniques (e.g. in vivo microdialysis, models of cerebral ischemia) as well as clinical studies we aim to obtain new information about possibilities to rescue brain tissue from ischemic injury. Regarding therapeutic options, we described inflammatory events in ischemic stroke or a paradoxal activation of the coagulation system in response to rt-PA thrombolysis of this disease. Closely related to these investigations on the field of cerebrovascular diseases are our studies on vascular dementia due to cerebral microangiopathy. E.g., we first described hyperhomocysteinaemia as a independent risk factor or cerebral microangiopathy (e.g., Faßbender et al., Lancet 1999). Closely related to these investigations on the field of cerebrovascular diseases are our studies on vascular dementia due to cerebral microangiopathy. E.g., we first described hyperhomocysteinaemia as a highly important, independent risk factor or cerebral microangiopathy (e.g., Faßbender et al., Lancet 1999).
| | | Stroke Management: "Mobile Stroke-Unit" for Reduction of the Response Time in Ischemic Stroke | | Currently, systemic thrombolysis with the tissue plasminogen activator represents the only causal and approved treatment for acute ischemic stroke. However, the chances to save the brain tissue by a thrombolytic therapy exponentially decrease with proceeding time after onset of symptoms. In most cases, the beginning of the thrombolysis therapy is delayed by a variety of factors, like delivery to the hospital, re-examinations and delay of CT scan. Due to this, a thrombolytic therapy is possible only in a minority of the stroke patients (2-5 %). In one study, we investigate whether a "Mobile Stroke Unit", a rescue car with an integrated CT scanner, contributes to a better stroke management by saving precious time until a therapeutic decision is made. This device allows prehospital diagnosis and therapy (thrombolysis). A monocentric, randomised prospective trial is currently performed (ClinicalTrials.gov Identifier: NCT00792220).
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Cooperation partners and support: Departments for Neuroradiology and Anaesthesiology of the Saarland University, German Red Cross, Meytec Information Systems GmbH, Else Kröner Fresenius Foundation, Mercedes-Benz AG, Stadt Homburg, Karlsberg GmbH, Rettungsstiftung Saarland, Rettungsdienst Logistik-Service GmbH, Saarland. | | | Multiple sclerosis | | On the field of MS we first described the secretion of the central proinflammatory cytokines in CSF (e.g. interleukin 12, interleukin 18) and the interaction between immunoactivation, neuroendocrine dysregulation (HPA-axis) and neuropsychiatric symptoms (e.g. major depression). Using experimental autoimmune encephalomyelitis (EAE), the animal model for MS, we are investigating the mechanism of the immigration of T-lymphocytes into the cerebral parenchyma as it plays a decisive role in MS pathogenesis. To gain access to the CNS, circulating T cells must first transverse the blood-brain barrier (BBB) via complex interactions between complementary adhesion molecules found at the surfaces of lymphocytes and endothelial cells. Once immigrated into the brain parenchyma, an intensive inflammatory reaction is induced, leading to myelin sheath and neuronal destruction. We investigate the role of the innate immune system and its receptors e.g. CD14, TLRs in these pathophysiological mechanisms. We were able to demonstrate that deficiency of CD14 alters EAE clinical features and inflammatory CNS infiltration. 
Fig. 3. CD14 deficiency enhances clinical features of active EAE. Average weight loss (a) and disease scores (b) of CD14 deficient mice and wt controls were calculated daily. CD14 deficient animals showed a significant increase of disease severity at the peak of clinical symptoms between days 18 20 (* p < 0.05). Recently, we observed that microglial inflammatory activity is strongly suppressed by their phagocytosis of myelin, the presumed target of the immune attack, via an enhanced p47-PHOX-mediated generation of reactive oxygen species (ROS) (Liu et al., J Neurosci, 2006). Thus, the view on ROS in MS is currently shifting from being considered exclusively detrimental cells toward having a more complex role in regulating inflammatory reactions. | | |
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