Growing evidence suggests a crucial role of neuroinflammation in the pathophysiology of Parkinson... more Growing evidence suggests a crucial role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Neuroinflammation is linked to the accumulation and aggregation of a-synuclein (αSyn), the primary pathological hallmark of PD. Toll-like receptors 4 (TLR4) can have implications in the development and progression of the pathology. In this study, we analyzed the expression of TLR4 in the substantia nigra (SN) and medial temporal gyrus (GTM) of well-characterized PD patients and age-matched controls. We also assessed the co-localization of TLR4 with pSer129 αSyn. Using qPCR, we observed an upregulation of TLR4 expression in the SN and GTM in PD patients compared to controls, which was accompanied by a reduction in αSyn expression likely due to the depletion of dopaminergic (DA) cells. Additionally, using immunofluorescence and confocal microscopy, we observed TLR4-positive staining and co-localization with pSer129-αSyn in Lewy bodies of DA neurons in the SN, as well as in...
Although various neurodegenerative disorders have been associated with coeliac disease (CD), the ... more Although various neurodegenerative disorders have been associated with coeliac disease (CD), the underlying neuropathological link between these brain and gut diseases remains unclear. We postulated that the neuronal damage sporadically observed in CD patients is immune-mediated. Our aim was to determine if the loss of neurons, especially Purkinje cells, coincides with microglia activation and T- and B-cell infiltration in the cerebellum of patients with CD and a concomitant idiopathic neurological disease affecting the cerebellum (NeuroCD). Post-mortem cerebellar tissue was collected of validated NeuroCD cases. Gender- and age-matched genetic spinocerebellar ataxia (SCA) controls and non-neurological controls (NNC) were selected based on clinical reports and pathological findings. Cerebellar tissue of seventeen patients was included (6 NeuroCD, 5 SCA, 6 NNC). In SCA cases we found that the Purkinje cell layer was 58.6% reduced in comparison with NNC. In NeuroCD cases this reduction...
This chapter summarizes and discusses the regulation of adult neurogenesis and hippocampal cellul... more This chapter summarizes and discusses the regulation of adult neurogenesis and hippocampal cellular plasticity by systemic factors. We focus on the role of stress, glucocorticoids, and related factors such as sleep deprivation and inflammation. THE CONCEPT OF STRESS Ever present as stress may be in the modern Western society, it represents an old, yet essential, alarm system for an organism. By definition, stress systems are activated whenever a discrepancy occurs between an organism’s expectations and the reality it encounters, particularly when it involves a threat to the organism’s homeostasis, well-being, or health. Lack of information, loss of control, unpredictability, and uncertainty when faced with predator threat in animals or psychosocial demands in humans can all produce stress signals. The same holds for perturbations of a physical or biological nature, such as food shortage, injury, or inflammation. Various sensory and cognitive signals converge to activate a stress res...
The advent of RNA‐sequencing techniques has made it possible to generate large, unbiased gene exp... more The advent of RNA‐sequencing techniques has made it possible to generate large, unbiased gene expression datasets of tissues and cell types. Several studies describing gene expression data of microglia from Alzheimer's disease or multiple sclerosis have been published, aiming to generate more insight into the role of microglia in these neurological diseases. Though the raw sequencing data are often deposited in open access databases, the most accessible source of data for scientists is what is reported in published manuscripts. We observed a relatively limited overlap in reported differentially expressed genes between various microglia RNA‐sequencing studies from multiple sclerosis or Alzheimer's diseases. It was clear that differences in experimental set up influenced the number of overlapping reported genes. However, even when the experimental set up was very similar, we observed that overlap in reported genes could be low. We identified that papers reporting large numbers...
TG2 and fibronectin protein expression in rat astrocytes and microglia. Untreated (Ctrl) and 48 h... more TG2 and fibronectin protein expression in rat astrocytes and microglia. Untreated (Ctrl) and 48 h LPS-treated primary rat astrocytes (A) expressed more fibronectin (FN) and more TG2 compared to untreated (Ctrl) and LPS-treated primary rat microglia (M). Representative blot of three independent experiments is shown. (TIFF 195 kb)
ABSTRACTDemyelination of the CNS is a prominent pathological hallmark of Multiple Sclerosis (MS) ... more ABSTRACTDemyelination of the CNS is a prominent pathological hallmark of Multiple Sclerosis (MS) and affects both white (WM) and grey matter (GM). However, demyelinated WM and GM areas exhibit clear pathological differences, most notably the presence or absence of inflammation and activated glial cells in WM and GM, respectively. In order to gain more insight into the differential pathology of demyelinated WM and GM areas, we micro-dissected neighbouring WM and GM demyelinated areas as well as normal appearing matter from leukocortical lesions of human post-mortem material and used these samples for RNA-sequencing. Our data show that even neighbouring WM and GM demyelinated areas share only 10% overlap in gene expression, implying a distinct gene expression profile, which is extending to a specific glial cell related signature. We propose that, based on their distinct expression profile, pathological processes in neighbouring WM and GM are likely different which could have implicati...
Additional file 1: Figure S1. Cell depth in μm of WM (blue, left of dotted line) and GM (red, rig... more Additional file 1: Figure S1. Cell depth in μm of WM (blue, left of dotted line) and GM (red, right of dotted line) enriched microglia after treatment with LPS, myelin or myelin+LPS. Black dots represent data from individual microglia, bars represent the mean and +/- SEM. Figure S2. Representative lightmicroscopical image of primary mixed glial cells cultured in ibidi μ-dish with grid used for indentation. Microglia are identified by IBA-1 immunoreactivity (pink), astrocytes are identified by GFAP immunoreactivity (brown). Scalebar = 250 μm. Figure S3. Graph depicting mRNA levels of Aif-1 and Gfap in WM (blue) and GM (red) derived mixed glial cell cultures. Black dots represent data from 3 individual cultures, bars represent the mean and +/- SEM. We observed no statistical differences in the mRNA expression of Aif-1 or Gfap between conditions (ns).
MS is regarded as a disease of the CNS where a combination of demyelination, inflammation, and ax... more MS is regarded as a disease of the CNS where a combination of demyelination, inflammation, and axonal degeneration results in neurologic disability. However, various studies have also shown that the peripheral nervous system (PNS) can be involved in MS, expanding the consequences of this disorder outside the brain and spinal cord, and providing food for thought to the still unanswered questions about MS origin and treatment. Here, we review the emerging concept of PNS involvement in MS by looking at it from a clinical, molecular, and biochemical point of view. Clinical, pathologic, electrophysiologic, and imaging studies give evidence that the PNS is functionally affected during MS and suggest that the disease might be part of a spectrum of demyelinating disorders instead of being a distinct entity. At the molecular level, similarities between the anatomic structure of the myelin and its interaction with axons in CNS and PNS are evident. In addition, a number of biochemical alterati...
Multiple Sclerosis (MS) is a debilitating disease and is characterized by demyelination of the ce... more Multiple Sclerosis (MS) is a debilitating disease and is characterized by demyelination of the central nervous system (CNS) resulting in the wide-spread formation of white matter lesions (WML) and grey matter lesions (GML). WML are pathologically characterized by the presence of immune cells that infiltrated into the CNS, whereas in GML these are hardly present. This striking pathological difference between WML and GML questions the underlying mechanism. It is known that infiltrating leukocytes contribute to the generation of WML, however, since GML show a paucity of infiltrating immune cells, their importance in GML formation remains to be determined. Here, we review pathological characteristics of WML and GML, and put forward some possible explanations for the observed pathological differences. In our view, cellular and molecular characteristics in WM and GM, and local differences residing within in WML and GML, in particular by glial cell populations and their molecules expressed...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1997
Peripheral administration of lipopolysaccharide (LPS) may activate the hypothalamus-pituitary-adr... more Peripheral administration of lipopolysaccharide (LPS) may activate the hypothalamus-pituitary-adrenal (HPA) axis by way of both neural and humoral mechanisms. We have investigated whether biologically active endotoxin appears in the general circulation after intraperitoneal administration of LPS (5 or 100 μg/kg) to rats and whether this is a prerequisite for activation of this HPA axis. Within 15 min, endotoxin appeared in the general circulation, whereas elevations of plasma adrenocorticotropic hormone (ACTH), corticosterone, and interleukin (IL)-6 concentrations were not detected until 90 min after LPS injection. At this time, a marked interindividual variation was observed in plasma concentrations of endotoxin, ACTH, corticosterone, and IL-6. Elevated levels of plasma endotoxin were associated with elevated levels of ACTH, corticosterone, and IL-6. Intravenous administration of the LPS antagonist cationic antimicrobial protein 18 (5 mg/kg), which did not affect cytokine productio...
Growing evidence suggests a crucial role of neuroinflammation in the pathophysiology of Parkinson... more Growing evidence suggests a crucial role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Neuroinflammation is linked to the accumulation and aggregation of a-synuclein (αSyn), the primary pathological hallmark of PD. Toll-like receptors 4 (TLR4) can have implications in the development and progression of the pathology. In this study, we analyzed the expression of TLR4 in the substantia nigra (SN) and medial temporal gyrus (GTM) of well-characterized PD patients and age-matched controls. We also assessed the co-localization of TLR4 with pSer129 αSyn. Using qPCR, we observed an upregulation of TLR4 expression in the SN and GTM in PD patients compared to controls, which was accompanied by a reduction in αSyn expression likely due to the depletion of dopaminergic (DA) cells. Additionally, using immunofluorescence and confocal microscopy, we observed TLR4-positive staining and co-localization with pSer129-αSyn in Lewy bodies of DA neurons in the SN, as well as in...
Although various neurodegenerative disorders have been associated with coeliac disease (CD), the ... more Although various neurodegenerative disorders have been associated with coeliac disease (CD), the underlying neuropathological link between these brain and gut diseases remains unclear. We postulated that the neuronal damage sporadically observed in CD patients is immune-mediated. Our aim was to determine if the loss of neurons, especially Purkinje cells, coincides with microglia activation and T- and B-cell infiltration in the cerebellum of patients with CD and a concomitant idiopathic neurological disease affecting the cerebellum (NeuroCD). Post-mortem cerebellar tissue was collected of validated NeuroCD cases. Gender- and age-matched genetic spinocerebellar ataxia (SCA) controls and non-neurological controls (NNC) were selected based on clinical reports and pathological findings. Cerebellar tissue of seventeen patients was included (6 NeuroCD, 5 SCA, 6 NNC). In SCA cases we found that the Purkinje cell layer was 58.6% reduced in comparison with NNC. In NeuroCD cases this reduction...
This chapter summarizes and discusses the regulation of adult neurogenesis and hippocampal cellul... more This chapter summarizes and discusses the regulation of adult neurogenesis and hippocampal cellular plasticity by systemic factors. We focus on the role of stress, glucocorticoids, and related factors such as sleep deprivation and inflammation. THE CONCEPT OF STRESS Ever present as stress may be in the modern Western society, it represents an old, yet essential, alarm system for an organism. By definition, stress systems are activated whenever a discrepancy occurs between an organism’s expectations and the reality it encounters, particularly when it involves a threat to the organism’s homeostasis, well-being, or health. Lack of information, loss of control, unpredictability, and uncertainty when faced with predator threat in animals or psychosocial demands in humans can all produce stress signals. The same holds for perturbations of a physical or biological nature, such as food shortage, injury, or inflammation. Various sensory and cognitive signals converge to activate a stress res...
The advent of RNA‐sequencing techniques has made it possible to generate large, unbiased gene exp... more The advent of RNA‐sequencing techniques has made it possible to generate large, unbiased gene expression datasets of tissues and cell types. Several studies describing gene expression data of microglia from Alzheimer's disease or multiple sclerosis have been published, aiming to generate more insight into the role of microglia in these neurological diseases. Though the raw sequencing data are often deposited in open access databases, the most accessible source of data for scientists is what is reported in published manuscripts. We observed a relatively limited overlap in reported differentially expressed genes between various microglia RNA‐sequencing studies from multiple sclerosis or Alzheimer's diseases. It was clear that differences in experimental set up influenced the number of overlapping reported genes. However, even when the experimental set up was very similar, we observed that overlap in reported genes could be low. We identified that papers reporting large numbers...
TG2 and fibronectin protein expression in rat astrocytes and microglia. Untreated (Ctrl) and 48 h... more TG2 and fibronectin protein expression in rat astrocytes and microglia. Untreated (Ctrl) and 48 h LPS-treated primary rat astrocytes (A) expressed more fibronectin (FN) and more TG2 compared to untreated (Ctrl) and LPS-treated primary rat microglia (M). Representative blot of three independent experiments is shown. (TIFF 195 kb)
ABSTRACTDemyelination of the CNS is a prominent pathological hallmark of Multiple Sclerosis (MS) ... more ABSTRACTDemyelination of the CNS is a prominent pathological hallmark of Multiple Sclerosis (MS) and affects both white (WM) and grey matter (GM). However, demyelinated WM and GM areas exhibit clear pathological differences, most notably the presence or absence of inflammation and activated glial cells in WM and GM, respectively. In order to gain more insight into the differential pathology of demyelinated WM and GM areas, we micro-dissected neighbouring WM and GM demyelinated areas as well as normal appearing matter from leukocortical lesions of human post-mortem material and used these samples for RNA-sequencing. Our data show that even neighbouring WM and GM demyelinated areas share only 10% overlap in gene expression, implying a distinct gene expression profile, which is extending to a specific glial cell related signature. We propose that, based on their distinct expression profile, pathological processes in neighbouring WM and GM are likely different which could have implicati...
Additional file 1: Figure S1. Cell depth in μm of WM (blue, left of dotted line) and GM (red, rig... more Additional file 1: Figure S1. Cell depth in μm of WM (blue, left of dotted line) and GM (red, right of dotted line) enriched microglia after treatment with LPS, myelin or myelin+LPS. Black dots represent data from individual microglia, bars represent the mean and +/- SEM. Figure S2. Representative lightmicroscopical image of primary mixed glial cells cultured in ibidi μ-dish with grid used for indentation. Microglia are identified by IBA-1 immunoreactivity (pink), astrocytes are identified by GFAP immunoreactivity (brown). Scalebar = 250 μm. Figure S3. Graph depicting mRNA levels of Aif-1 and Gfap in WM (blue) and GM (red) derived mixed glial cell cultures. Black dots represent data from 3 individual cultures, bars represent the mean and +/- SEM. We observed no statistical differences in the mRNA expression of Aif-1 or Gfap between conditions (ns).
MS is regarded as a disease of the CNS where a combination of demyelination, inflammation, and ax... more MS is regarded as a disease of the CNS where a combination of demyelination, inflammation, and axonal degeneration results in neurologic disability. However, various studies have also shown that the peripheral nervous system (PNS) can be involved in MS, expanding the consequences of this disorder outside the brain and spinal cord, and providing food for thought to the still unanswered questions about MS origin and treatment. Here, we review the emerging concept of PNS involvement in MS by looking at it from a clinical, molecular, and biochemical point of view. Clinical, pathologic, electrophysiologic, and imaging studies give evidence that the PNS is functionally affected during MS and suggest that the disease might be part of a spectrum of demyelinating disorders instead of being a distinct entity. At the molecular level, similarities between the anatomic structure of the myelin and its interaction with axons in CNS and PNS are evident. In addition, a number of biochemical alterati...
Multiple Sclerosis (MS) is a debilitating disease and is characterized by demyelination of the ce... more Multiple Sclerosis (MS) is a debilitating disease and is characterized by demyelination of the central nervous system (CNS) resulting in the wide-spread formation of white matter lesions (WML) and grey matter lesions (GML). WML are pathologically characterized by the presence of immune cells that infiltrated into the CNS, whereas in GML these are hardly present. This striking pathological difference between WML and GML questions the underlying mechanism. It is known that infiltrating leukocytes contribute to the generation of WML, however, since GML show a paucity of infiltrating immune cells, their importance in GML formation remains to be determined. Here, we review pathological characteristics of WML and GML, and put forward some possible explanations for the observed pathological differences. In our view, cellular and molecular characteristics in WM and GM, and local differences residing within in WML and GML, in particular by glial cell populations and their molecules expressed...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1997
Peripheral administration of lipopolysaccharide (LPS) may activate the hypothalamus-pituitary-adr... more Peripheral administration of lipopolysaccharide (LPS) may activate the hypothalamus-pituitary-adrenal (HPA) axis by way of both neural and humoral mechanisms. We have investigated whether biologically active endotoxin appears in the general circulation after intraperitoneal administration of LPS (5 or 100 μg/kg) to rats and whether this is a prerequisite for activation of this HPA axis. Within 15 min, endotoxin appeared in the general circulation, whereas elevations of plasma adrenocorticotropic hormone (ACTH), corticosterone, and interleukin (IL)-6 concentrations were not detected until 90 min after LPS injection. At this time, a marked interindividual variation was observed in plasma concentrations of endotoxin, ACTH, corticosterone, and IL-6. Elevated levels of plasma endotoxin were associated with elevated levels of ACTH, corticosterone, and IL-6. Intravenous administration of the LPS antagonist cationic antimicrobial protein 18 (5 mg/kg), which did not affect cytokine productio...
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