Jan-Philipp Bach

Role of MIF in Inflammation and Tumorigenesis

MIF has been described as a protein that plays an essential role in both innate and acquired immunity. Previous studies have demonstrated that MIF activates lymphocytes, granulocytes and monocytes/macrophages. Furthermore, MIF can counteract the physiological function of steroids, thus playing a role in immune system regulation. Further evidence for a role of MIF in immunity was obtained in mouse models of autoimmune disorders, where the inhibition of MIF resulted in a more benign disease progression. This observation made MIF an attractive therapeutic target for the treatment of these disorders. Moreover, MIF expression was found to be upregulated in a variety of different tumor cells, a finding that further attracted interest. This review provides an overview of the involvement of MIF in both autoimmune disorders and tumorigenesis and summarizes the molecular action of MIF in this context.

Projected numbers of people with movement disorders in the years 2030 and 2050

Movement disorders are chronic diseases with an increasing prevalence in old age. Because these disorders pose a major challenge to patients, families, and health care systems, there is a need for reliable data about the future number of affected people.

The Role of Macrophage Inhibitory Factor in Tumorigenesis and Central Nervous System Tumors

Macrophage migration inhibitory factor (MIF) has been described as a protein that plays an important role in both innate and acquired immunity. Further research has shown that MIF plays a particularly critical part in cell cycle regulation and therefore in tumorigenesis as well. Over the past few years, the significance of the role of MIF in a variety of both solid and hematologic tumors has been established. More recently, interest has increased in the role of MIF in the development of central nervous system (CNS) tumors, in which it appears to influence cell cycle control. In addition, MIF has been identified as an essential actor in metastasis and angiogenesis. Vascular growth factor concentration raises because of increased levels of MIF in brain tumors. Recently, the MIF receptor complex has been described, and it appears that this may be a suitable drug target for treatment of brain tumors. In light of these findings, the authors chose to conduct a systematic search for information regarding MIF that has been published within the past 15 years using the terms “inflammation,” “glioblastoma,” “brain tumor,” “astrocytoma,” “microglia,” “glioblastoma,” “immune system and brain tumors,” “glioblastoma and MIF,” and “brain tumor and MIF.” The aim of this article was thus to present a detailed review of current knowledge regarding the role of MIF in CNS tumor pathophysiology. Cancer 2009.

Pathogenic and physiological autoantibodies in the central nervous system.

Summary:  In this article, we review the current knowledge on pathological and physiological autoantibodies directed toward structures in the central nervous system (CNS) with an emphasis on their regulation and origin. Pathological autoantibodies in the CNS that are associated with autoimmunity often lead to severe neurological deficits via inflammatory processes such as encephalitis. In some instances, however, autoantibodies function as a marker for diagnostic purposes without contributing to the pathological process and/or disease progression. The existence of naturally occurring physiological autoantibodies has been known for a long time, and their role in maintaining homeostasis is well established. Within the brain, naturally occurring autoantibodies targeting aggregated proteins have been detected and might be promising candidates for new therapeutic approaches for neurodegenerative disorders. Further evidence has demonstrated the existence of naturally occurring antibodies targeting antigens on neurons and oligodendrocytes that promote axonal outgrowth and remyelination. The numerous actions of physiological autoantibodies as well as their regulation and origin are summarized in this review.

Impact of complications and comorbidities on treatment costs and health-related quality of life of patients with Parkinson's disease

BACKGROUND Data regarding both drug-related and non-drug-related costs in patients with Parkinsons disease (PD) are scarce, mainly due to the difficulties in data acquisition in experimental designs. Likewise, the reported impact of drug costs on total direct costs varies across different studies. In addition, the influence of comorbidities on both treatment costs and health-related quality of life has not been adequately evaluated. METHODS A sample of office-based neurologists (n=315) in Germany was asked to examine up to five consecutive patients with PD (n=1449) on a specified day during the study period. Patients of all ages were eligible and their evaluation was performed using standardized questionnaires. RESULTS PD-specific therapy costs increased with the stage of the disease, early onset of the disease and disease duration. The major costs were due to PD-related therapy, whereas other medications only resulted in minor costs. Disease stage mainly influenced direct therapy costs, with an observed increase of total daily costs from €7.3 to €11.3/day. In addition, disease onset at age <65 years resulted in total daily costs of €11.2 compared to late onset of disease (>75 years) with daily therapy costs of €5.3. In this patient group neuropsychiatric comorbidities such as dementia and depression were only insufficiently treated. In addition, these comorbidities severely affected health-related quality of life. CONCLUSION Therapy costs were influenced by disease stage, disease onset as well as present comorbidities. Furthermore, comorbidities such as depression and dementia were diagnosed but were not adequately treated.

The role of CNI-1493 in the function of primary microglia with respect to amyloid-β.

Amyloid-β (Aβ) oligomer toxicity is a crucial factor in the development of Alzheimers disease. Therefore, the aim of therapeutic research is to target the modification of secretase activity, increase Aβ degradation, reduce Aβ formation, and modulate Aβ-induced neuroinflammation. Recently, the p38 MAP kinase inhibitor CNI-1493 has been shown to reduce plaque load and has led to an improvement in memory performance in a transgenic mouse model. We examined the role of CNI-1493 in the microglial inflammatory response to Aβ using both a microglia cell line as well as primary microglia isolated from mesocortices. MTT assays were performed to quantify cell viability. FACS analysis was used to measure phagocytosis. We used ELISA to analyse cytokine concentrations in response to CNI-1493 treatment. Western-blot/Dot-blot techniques were used to show the interaction of CNI-1493 with Aβ-oligomers as well as to measure apoptosis in microglia cells. RT-PCR was used to analyze secretase expression, and secretase function was determined using fluorimetric assays. CNI-1493 is able to prevent oligomer formation as well as apoptosis in microglia. A significant reduction was found in the Aβ-induced release of IL-6 and TNF-α in the presence of CNI-1493. Phagocytosis is an essential Aβ removal mechanism and was enhanced by CNI-1493 in primary microglia. CNI-1493 also influenced the α-secretase product C83 with an increase in the treated cells, while a simultaneous reduction in Aβ secretion was also observed. We hypothesize that CNI-1493 not only reduces neuroinflammation and consequent neurodegeneration, but also leads to a shift in AβPP-processing towards the non-amyloidogenic pathway. Therefore, CNI-1493 is a promising candidate for the treatment of AD.

Naturally Occurring Autoantibodies Against β-Amyloid

Naturally occurring antibodies (NAbs) have been described for more than 30 years. Recently, NAbs against β-Amyloid and against other proteins involved in neurodegenerative disorders have been detected in humans. Based on the current evidence, it is hypothesized that anti-Aβ NAbs can inhibit the fibrillation and toxicity of β-aymloid, can improve cognition in a transgenic mouse model and interfere with oligomers of Aβ. Different functions of these NAbs have been described in the current literature. Based on the results of the diverse studies a Phase-III study using IVIG has been initiated in patients with AD. The results will show whether the application of NAbs will change the fate of the disease. This chapter summarizes our current knowledge on NAbs against Aβ.

Mechanisms of action of naturally occurring antibodies against β-amyloid on microglia.

BackgroundNaturally occurring autoantibodies against amyloid-β (nAbs-Aβ) have been shown to exert beneficial effects on transgenic Alzheimer’s disease (AD) animals in vivo and on primary neurons in vitro. Not much is known about their effect on microglial cells. Our aim was to investigate the effect of nAbs-Aβ on amyloid-β (Aβ)-treated microglial cells in vitro with respect to cell viability, stress pathways, cytokine production and phagocytotic abilities and whether these effects can be conveyed to neurons.MethodsPrimary microglial cells isolated from Swiss Webster mouse mesencephalons on embryonic day 13.5 were pretreated with nAbs-Aβ and then treated with Aβ oligomers. After 3 hours, phagocytosis as well as western blot analysis were evaluated to measure the amount of phagocytized Aβ. Cell viability was analyzed using an MTT assay 24 hours after treatment. Pro-inflammatory cytokines in the supernatants were analyzed with ELISAs and then we treated primary neuronal cells with these conditioned microglia supernatants. Twenty-four hours later we did a MTT assay of the treated neurons. We further investigated the effect of a single nAbs-Aβ administration on Tg2576 mice in vivo.ResultsUpon co-administration of Aβ and nAbs-Aβ no change in microglia viability was observed. However, there was an increase in phosphorylated p38 protein level, an increase in the pro-inflammatory cytokines TNF-α and IL-6 and an increase in Aβ uptake by microglial cells. Treatment of primary neurons with conditioned microglia medium led to a 10% improvement in cell viability when nAbs-Aβ were co-administered compared to Aβ-treated cells alone. We were unable to detect changes in cytokine production in brain lysates of Tg2576 mice.ConclusionsWe provide evidence on the mechanism of action of nAbs-Aβ on microglia in vitro. Interestingly, our in vivo data indicate that nAbs-Aβ administration should be considered as a therapeutic strategy in AD, since there is no inflammatory reaction.

Health-Related Quality of Life in Patients with a History of Myocardial Infarction and Stroke

Background: There is a lack of the generic data comparing the influence of different diseases on health-related quality of life (HrQoL) in a representative sample of primary care patients. Methods: Patient data were collected in the DETECT (Diabetes Cardiovascular Risk Evaluation: Targets and Essential Data for Commitment of Treatment) study including 55,000 patients. Results: 3,109 patients (33.3% female) with myocardial infarction (MI), stroke or both were compared to patients with a wide range of other diagnoses. Stroke and MI patients revealed a lower HrQoL as compared to patients with other diagnoses. Stroke was associated with strongest quality of life reduction. Multivariate analysis revealed several different determining factors. Conclusions: The reduction of HrQoL of patients with MI and stroke is primarily determined by the CNS insult. These data provide further evidence that early diagnosis and treatment of cardiovascular risk factors is essential to reduce subsequent stroke.

α1-antitrypsin modulates microglial-mediated neuroinflammation and protects microglial cells from amyloid-β-induced toxicity.

BackgroundOne hallmark of Alzheimer disease is microglial activation. Therapeutic approaches for this neurodegenerative disease include the modulation of microglial cells. α1-antitrypsin (A1AT) has been shown to exert anti-inflammatory effects on macrophages and lung epithelial cells and an inhibition of calpain activity in neutrophil granulocytes. Nothing is known about the effect of A1AT on microglial-mediated neuroinflammation. Our aim was to investigate the effect of A1AT on amyloid-β (Aβ)- and LPS-treated microglial cells in vitro with respect to cytokine production, stress pathways, cell viability, phagocytotic abilities and the underlying mechanisms.MethodsPrimary microglial cells were isolated from Swiss Webster mouse embryos on embryonic day 13.5. Cytokines in the supernatants of treated primary microglial cells were analyzed with ELISAs, and accumulated nitrite was detected with Griess reagents. Intracellular stress pathways were investigated in cell lysates using western blotting. Intracellular calcium levels were detected in BV-2 microglial cells loaded with the Ca2+-sensitive (fluorescent) dye Fluo-4. Calpain activity in primary microglial cells was assessed by using a calpain activity assay. Cell viability of Aβ-treated microglial cells was analyzed using MTT assay. Phagocytosis of Aβ was evaluated with western blot analysis.ResultsUpon co-administration, A1AT reduced pro-inflammatory mediators induced by LPS or Aβ. Interestingly, we detected a reduction in calpain activity and in the concentration of intracellular calcium that might mediate the anti-inflammatory effects of A1AT. Inhibition of the classic activation pathways, such as phosphorylation of mitogen-activated protein kinases or activation of protein kinase A were excluded as a mechanism of A1AT-mediated effects. In addition, A1AT increased the viability of Aβ-treated microglial cells and reduced Aβ phagocytosis.ConclusionsWe provide evidence on the mechanism of action of A1AT on microglial-mediated neuroinflammation in vitro. Our in vitro data indicate that A1AT treatment modulates microglial cells in inflammatory conditions and that this modulation is due to an inhibition of calpain activity and intracellular calcium levels. The underlying mechanisms of the effects observed here are promising for future therapeutic strategies and should thus be further pursued in transgenic mouse models of Alzheimer disease.