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Biomedical subjects

R Veerhuis

Publications and source records attributed to R Veerhuis.

At least 19 recordsLinked to original sources
PubMed2006

The significance of neuroinflammation in understanding Alzheimer's disease.

The interest of scientists in the involvement of inflammation-related mechanisms in the pathogenesis of Alzheimer's disease (AD) goes back to the work of one of the pioneers of the study of this disease. About hundred years ago Oskar Fischer stated that the crucial step in the plaque formation is the extracellular deposition of a foreign substance that provokes an inflammatory reaction followed by a regenerative response of the surrounding nerve fibers. Eighty years later immunohistochemical studies revealed that amyloid plaques are indeed co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. These findings have led to the view that the amyloid plaque is the nidus of a non-immune mediated chronic inflammatory response locally induced by fibrillar A beta deposits. Recent neuropathological studies show a close relationship between fibrillar A beta deposits, inflammation and neuroregeneration in relatively early stages of AD pathology preceding late AD stages characterized by extensive tau-related neurofibrillary changes. In the present work we will review the role of inflammation in the early stage of AD pathology and particularly the role of inflammation in A beta metabolism and deposition. We also discuss the possibilities of inflammation-based therapeutic strategies in AD.

Alzheimer Disease↗
PubMed2005

Neuroinflammation and regeneration in the early stages of Alzheimer's disease pathology.

The initial stages of Alzheimer's disease pathology in the neocortex show upregulation of cell cycle proteins, adhesion and inflammation related factors, indicating the early involvement of inflammatory and regenerating pathways in Alzheimer's disease pathogenesis. These brain changes precede the neurofibrillary pathology and the extensive process of neurodestruction and (astro)gliosis. Amyloid beta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mouse models harbouring the pathological Alzheimer's disease mutations, while neurodegenerative characteristics are not seen in these models. This review will discuss the relationship between neuroinflammation and neuroregeneration in the early stages of Alzheimer's disease pathogenesis.

Alzheimer Disease↗
PubMed2005

The unfolded protein response is activated in Alzheimer's disease.

Alzheimer's disease (AD) is, at the neuropathological level, characterized by the accumulation and aggregation of misfolded proteins. The presence of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR) that may protect the cell against the toxic buildup of misfolded proteins. In this study we investigated the activation of the UPR in AD. Protein levels of BiP/GRP78, a molecular chaperone which is up-regulated during the UPR, was found to be increased in AD temporal cortex and hippocampus as determined by Western blot analysis. At the immunohistochemical level intensified staining of BiP/GRP78 was observed in AD, which did not co-localize with AT8-positive neurofibrillary tangles. In addition, we performed immunohistochemistry for phosphorylated (activated) pancreatic ER kinase (p-PERK), an ER kinase which is activated during the UPR. p-PERK was observed in neurons in AD patients, but not in non-demented control cases and did not co-localize with AT8-positive tangles. Overall, these data show that the UPR is activated in AD, and the increased occurrence of BiP/GRP78 and p-PERK in cytologically normal-appearing neurons suggest a role for the UPR early in AD neurodegeneration. Although the initial participation of the UPR in AD pathogenesis might be neuroprotective, sustained activation of the UPR in AD might initiate or mediate neurodegeneration.

Adult↗
PubMed2005

Amyloid associated proteins in Alzheimer's and prion disease.

Clustering of activated microglia in Abeta deposits is related to accumulation of amyloid associated factors and precedes the neurodegenerative changes in AD. Microglia-derived pro-inflammatory cytokines are suggested to be the driving force in AD pathology. Inflammation-related proteins, including complement factors, acute-phase proteins, pro-inflammatory cytokines, that normally are locally produced at low levels, are increasingly synthesized in Alzheimer's disease (AD) brain. Similar to AD, in prion diseases (Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and experimentally scrapie infected mouse brain) amyloid associated factors and activated glial cells accumulate in amyloid deposits of conformational changed prion protein (PrPres). Biological properties of Abeta and prion (PrP) peptides, including their potential to activate microglia, relate to Abeta and PrP peptide fibrillogenic abilities that are influenced by certain amyloid associated factors. However, since small oligomers of amyloid forming peptides are more toxic to neurons than large fibrils, certain amyloid associated factors that enhance fibril formation, may sequester the potentially harmful Abeta and PrP peptides from the neuronal microenvironment. In this review the positive and negative actions of amyloid associated factors on amyloid peptide fibril formation and on the fibrillation state related activation of microglia will be discussed. Insight in these mechanisms will enable the design of specific therapies to prevent neurodegenerative diseases in which amyloid accumulation and glial activation are prominent early features.

Alzheimer Disease↗
PubMed2004

C-reactive protein and complement depositions in human infarcted myocardium are more extensive in patients with reinfarction or upon treatment with reperfusion.

BACKGROUND: Impaired perfusion of the heart induces a local inflammatory response, which involves deposition of C-reactive protein and complement activation products C3d and C5b-9. We investigated whether reperfusion or reinfarction enhances these phenomena in humans. MATERIALS AND METHODS: Depositions of C-reactive protein and complement were quantified in tissue samples of infarcted myocardium from 76 patients who had died after acute myocardial infarction. The extent of depositions in patients treated with reperfusion or suffering from reinfarction was compared with that in patients who had no reperfusion or reinfarction. RESULTS: Patients with reinfarction had significantly more extensive depositions of C-reactive protein and complement (C3d and C5b-9) in the infarcted myocardium than patients without reinfarction. Similarly, patients who received reperfusion therapy had more extensive depositions also than those who had not received this therapy. CONCLUSIONS: Both reinfarction and reperfusion therapy significantly increase the extent of C-reactive protein and complement depositions in human myocardial infarcts.

Aged↗
PubMed2003

Decreased lysophosphatidylcholine/phosphatidylcholine ratio in cerebrospinal fluid in Alzheimer's disease.

Choline containing phospholipids are essential for the integrity of the'cell'membrane. Minor changes in the lysophosphatidylcholine (lyso-PC)/phosphatidylcholine (PC) ratio may lead to neuronal damage and cell loss. Several studies have shown protein and lipid oxidation in Alzheimer's disease (AD) affected brain regions. Amyloid-beta peptides may induce free-radical oxidative stress which normally is counteracted by anti-oxidant defense mechanisms. We hypothesize that oxidation may lead to changed concentrations of choline containing phospholipids in cerebrospinal fluid (CSF) of AD patients, because of the susceptibility of the unsaturated acyl-chains of PC for oxidation. PC and lyso-PC were determined in CSF of AD patients (n=19) and subjects with subjective memory complaints without dementia (n=19) by tandem mass spectrometry. No differences in total PC concentrations were observed between both study groups. Furthermore, we could not demonstrate different concentrations of PC species containing linoleic acid and PC species containing arachidonic acid. Interestingly, lyso-PC concentrations tended to be lower while the lyso-PC/PC ratio was significantly decreased in CSF of AD patients compared to controls (0.36% versus 0.54%; P=0.017). A comparable decrease was found for the lyso-PC/PC ratio for PC containing linoleic acid (P=0.022) or arachidonic acid (P=0.010), respectively. The lower lyso-PC/PC ratio in CSF of patients with AD may reflect alterations in the metabolism of choline-containing phospholipids in the brain in AD, and suggests that PC species containing linoleic acid or arachidonic acid are equally involved.

Alzheimer Disease↗
PubMed2002

Neuroinflammation in Alzheimer's disease and prion disease.

Alzheimer's disease (AD) and prion disease are characterized neuropathologically by extracellular deposits of Abeta and PrP amyloid fibrils, respectively. In both disorders, these cerebral amyloid deposits are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase protein, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the cerebral Abeta and PrP deposits are closely associated with a locally induced, non-immune-mediated chronic inflammatory response. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins, which are associated with Abeta plaques, are genetic risk factors for AD. Transgenic mice studies have established the role of amyloid associated acute-phase proteins in Alzheimer amyloid formation. In contrast to AD, there is a lack of evidence that cytokines and acute-phase proteins can influence disease progression in prion disease. Clinicopathological and neuroradiological studies have shown that activation of microglia is a relatively early pathogenetic event that precedes the process of neuropil destruction in AD patients. It has also been found that the onset of microglial activation coincided in mouse models of prion disease with the earliest changes in neuronal morphology, many weeks before neuronal loss and subsequent clinical signs of disease. In the present work, we review the similarities and differences between the involvement of inflammatory mechanisms in AD and prion disease. We also discuss the concept that the demonstration of a chronic inflammatory-like process relatively early in the pathological cascade of both diseases suggests potential therapeutic strategies to prevent or to retard these chronic neurodegenerative disorders.

Acute-Phase Proteins↗
PubMed2002

CSF markers related to pathogenetic mechanisms in Alzheimer's disease.

Serum amyloid P component (SAP) and complement C1q are found highly co-localized with extracellular fibrillar amyloidbeta (Abeta) deposits in Alzheimer's disease (AD) brain. Conflicting data were reported earlier about the cerebrospinal fluid (CSF) levels of SAP and C1q in AD compared to controls. The objective of the present study was to compare the levels of Abeta(1-42), tau, C1q and SAP in CSF of a well characterized group of AD patients and controls, and to assess the association with dementia severity. Significantly decreased CSF levels of Abeta(1-42) were observed in the AD group (480 +/- 104 ng/L) as compared to controls (1,040 +/- 213 ng/L), whereas tau levels were significantly higher in patients with AD (618 +/- 292 ng/L) than in controls (277 +/- 136 ng/L). Combining the results of Abeta(1-42) and tau measurements resulted in a clear separation between the AD group and the controls. No significant differences in CSF levels of SAP and C1q were observed between the well characterized AD patients and non demented control group. Furthermore, we could not demonstrate a correlation between SAP and C1q CSF levels and the severity of the disease, expressed in Mini-Mental State Examination (MMSE) scores. Therefore, in our opinion these factors can be excluded from the list of potentially interesting biomarkers for AD diagnosis and progression.

Aged↗
PubMed2001

Establishment of microglial cell cultures derived from postmortem human adult brain tissue: immunophenotypical and functional characterization.

Cell cultures have become an integral part of the daily routine in most biological research laboratories. Because they are very dynamic and highly accessible, cell cultures permit direct experimental manipulations where cause-effect relations can be more definitely assayed. We have developed cultures of microglial cells from rapid autopsies (range 3-10 hours) of nondemented elderly patients and Alzheimer's disease patients. Cultures were derived from the subcortical white matter, corpus callosum, and frontal, temporal, and occipital cortex. The adherent microglial cells were immunoreactive for CD68, CD45, CD11c, and major histocompatibility complex (MHC) class II markers, and were not immunoreactive for astrocyte or oligodendrocyte markers. In addition, some functional characteristics of the isolated microglial cells were also studied. Upon stimulation with lipopolysaccharide (LPS), microglial cells secreted pro- and antiinflammatory mediators, i.e., interleukin- (IL)-6, prostaglandin E2 (PGE2), and IL-10, indicating the functional capacity of cultured microglia.

Aged↗
PubMed2001

Cyclooxygenase expression in microglia and neurons in Alzheimer's disease and control brain.

Epidemiological studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) lower the risk of developing Alzheimer's disease (AD). Most NSAIDs act upon local inflammatory events by inhibiting the expression or activation of cylooxygenase (COX). In the present study the expression of COX-1 and COX-2 in AD and non-demented control temporal and frontal cortex was investigated using immunohistochemistry. COX-1 expression was detected in microglial cells, while COX-2 expression was found in neuronal cells. In AD brains, COX-1-positive microglial cells were primarily associated with amyloid beta plaques, while the number of COX-2-positive neurons was increased compared to that in control brains. No COX expression was detected in astrocytes. In vitro, primary human microglial and astrocyte cultures, and human neuroblastoma cells (SK-N-SH) were found to secrete prostaglandin E2 (PGE2), especially when stimulated. PGE2 synthesis by astrocytes and SK-N-SH cells was stimulated by interleukin-1beta. Microglial cell PGE2 synthesis was stimulated by lipopolysaccharide only. Although astrocytes are used in studies in vitro to investigate the role of COX in AD, there are no indications that these cells express COX-1 or COX-2 in vivo. The different distribution patterns of COX-1 and COX-2 in AD could implicate that these enzymes are involved in different cellular processes in the pathogenesis of AD.

Aged↗
PubMed2001

Interleukin-1beta induced cyclooxygenase 2 expression and prostaglandin E2 secretion by human neuroblastoma cells: implications for Alzheimer's disease.

Non-steroidal anti-inflammatory drugs (NSAIDs) may decrease the risk of developing Alzheimer's disease (AD). Cyclooxygenase 2 (COX-2), one of the targets of NSAIDs, is increasingly expressed in neuronal cells in AD brain. In this study, of the cytokines that are found at increased levels in AD brain (interleukin (IL)-1alpha, IL-1beta, IL-6 and tumour necrosis factor (TNF)alpha), IL-1beta was found to induce COX-2 immunoreactivity and prostaglandin (PG) E2 secretion by human neuroblastoma cell line SK-N-SH. COX inhibitors indomethacin and BF389, as well as the glucocorticoid dexamethasone (DEX) and pyrrolidinedithiocarbamate, which is an inhibitor of nuclear factor kappaB as well as a potent antioxidant, inhibited IL-1beta induced PGE2 secretion. In addition, DEX reduced the IL-1beta induced COX-2 immunoreactivity in the same concentration as wherein it inhibited PGE2 secretion. Palmitoyl trifluormethyl ketone, an inhibitor of Ca(2+) independent phospholipase A2 (iPLA2) and a less potent inhibitor of cytosolic PLA2, dose-dependently reduced the IL-1beta induced PGE2 secretion. This suggests that the IL-1beta induced PGE2 secretion may depend on the availability of arachidonic acid. Although the physiological role of neuronal COX-2 still remains unclear, we suggest an interplay between glial derived IL-1 and neuronal upregulation of COX-2 expression in chronic neurodegenerative diseases, such as AD.

Alzheimer Disease↗
PubMed2001

Immunological aspects of alzheimer's disease: therapeutic implications.

Alzheimer's disease (AD) is a chronic neurodegenerative disease causing progressive impairment of memory and cognitive function. The amyloid cascade hypothesis suggests that mismetabolism of the beta-amyloid (A beta) precursor protein (APP) followed by subsequent formation of non-fibrillar and fibrillar A beta deposits leads to glial activation and eventually to neurotoxicity, causing cognitive impairment. Several lines of evidence indicate that an inflammatory process contributes to the pathology of AD. First, inflammatory proteins have been identified as being associated with neuritic plaques and in glial cells surrounding these plaques. Second, certain polymorphisms of acute-phase proteins and cytokines associated with AD plaques increase the risk or predispose for earlier onset of developing AD. Third, epidemiological studies indicate that anti-inflammatory drugs can retard the development of AD. Several steps in the pathological cascade of AD have been identified as possible targets for actions of nonsteroidal anti-inflammatory drugs. For instance, microglia are considered a target because this cell type is closely involved in AD pathology through secretion of neurotoxic substances and by modulating a positive feedback loop of the inflammatory mechanism that may be involved in the pathological cascade in AD. On the basis of studies in APP transgenic mice, immunisation with A beta was recently suggested as a novel immunological approach for the treatment of AD. Immunisation elicits A beta-specific antibodies that could affect several early steps of the amyloid-driven cascade. Antibodies could prevent A beta from aggregating into fibrils and accelerate clearance of A beta by stimulating its removal by microglial cells. This review outlines the pathological and genetic evidence that an inflammatory mechanism is involved in AD and the therapeutic approaches based on inhibition or mediation of inflammation.

Alzheimer Disease↗
PubMed2000

Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1-40 and Abeta1-42 by human astrocytes.

Chronic inflammation and astrocytosis are characteristic histopathological features of Alzheimer's Disease (AD). Astrocytes are one of the predominant cell types in the brain. In AD they are activated and produce inflammatory components such as complement components, acute phase proteins, and cytokines. In this study we analyzed the effect of cytokines on the production of amyloid beta (Abeta) in the astrocytoma cell line U373 and in primary human astrocytes isolated postmortem from healthy aged persons as well as from patients with AD. Astrocytes did not produce Abeta in the absence of stimuli or following stimulation with IL-1beta, TNFalpha, IL-6, and TGF-beta1. Neither did combinations of TNFalpha and IL-1beta, IL-6 or TGF-beta1, or the coadministration of IFNgamma and IL-6 or TGF-beta1 induce Abeta production. In contrast, pronounced production of Abeta1-40 and Abeta1-42 was observed when primary astrocytes or astrocytoma cells were stimulated with combinations of IFNgamma and TNFalpha or IFNgamma and IL-1beta. Induction of Abeta production was accompanied by decreased glycosylation of APP as well as by increased secretion of APPsbeta. Our results suggest that astrocytes may be an important source of Abeta in the presence of certain combinations of inflammatory cytokines. IFNgamma in combination with TNFalpha or IL-1beta seems to trigger Abeta production by supporting beta-secretase cleavage of the immature APP molecule.

Aged↗
PubMed2000

Isolation and characterization of adult microglial cells and oligodendrocytes derived from postmortem human brain tissue.

The present study provides a detailed description of the simultaneous establishment and immunocytochemical characterization of highly enriched human adult microglial cell cultures as well as of oligodendrocyte cultures. For this study, brain tissue specimens were collected at autopsy with relatively short postmortem times (3-9 h) from various regions of the CNS of Alzheimer's disease, Pick's disease and non-demented control cases. Although methods to isolate viable glial cells from human adult brain tissue have been described, these human brain specimens were often derived from surgical resections, i.e., in order to treat intractable epilepsy, brain tumors or cardiovascular diseases involving the brain. However, for the study of many neurological disorders, surgical material is not available. Furthermore, for obvious reasons, there is a limit to the number of central nervous system (CNS) regions from which (enough) tissue can be obtained at surgery. The adherent primary microglial cells, isolated according to the here described procedures consisted of proliferating, phagocytotic cells that expressed various microglia/macrophage-specific markers as judged by immunocytochemical analysis. Non-adherent cells isolated from the same brain tissue samples expressed oligodendrocyte-specific markers. The current described culture system may provide a valuable tool in studying human CNS biology and disease.

Aged↗
PubMed2000

Neuroinflammation and Alzheimer disease: clinical and therapeutic implications.

In Alzheimer disease brains, the amyloid plaques are closely associated with a locally induced, nonimmune-mediated, chronic inflammatory response without any apparent influx of leukocytes from the blood. The present findings indicate that in cerebral A beta diseases (Alzheimer disease, Down syndrome, hereditary cerebral hemorrhage with amyloidosis-Dutch type), the clinical symptoms are determined to a great extent by the site of inflammatory response. It was found that the formation of the amyloid-microglia complex seems to be a relatively early pathogenic event that precedes the process of severe destruction of the neuropil. The idea that inflammation is implicated in Alzheimer pathology has received support from the epidemiologic studies indicating that the use of anti-inflammatory drugs can prevent or retard the Alzheimer disease process. In this contribution, we review the relationship between inflammation and clinical manifestation and the opportunities for anti-inflammatory treatments in Alzheimer disease.

Alzheimer Disease↗
PubMed1999

Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor.

Complement activation products C1q, C4c/d, and C3c/d in amyloid plaques in Alzheimer's disease probably result from direct binding and activation of C1 by amyloid beta peptides. RT-PCR and in situ hybridization studies have shown that several complement factors are produced in the brain parenchyma. In the present study, cytokines that can be detected in amyloid plaques (i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha) were found to differentially stimulate the expression of C1 subcomponents, C1-Inhibitor (C1-Inh), C4, and C3, by astrocyte and microglial cell cultures derived from postmortem adult, human brain specimens and by neuroblastoma cell lines in culture. C1r and C1s were secreted at low levels by astrocytes and neuroblastoma cell lines. Exposure of cells to IL-1 alpha, IL-1 beta, TNF-alpha and to a far lesser extent IL-6, markedly upregulated C1r, C1s, and C3 production. C4 synthesis increased in response to interferon (IFN)-gamma and IL-6, whereas that of C1-Inh could be stimulated only by IFN-gamma. Thus, C1-Inh production is refractory to stimulation by plaque-associated cytokines, whereas these cytokines do stimulate C1r, C1s, and also C4 and C3 secretion by astrocytes and neuronal cells in culture. In contrast to the amyloid plaque associated cytokines IL-1 beta, IL-1 alpha, and TNF-alpha, the amyloid peptide A beta 1-42 itself did not stimulate C1r and C1s synthesis by astrocytes, microglial cells, or neuroblastoma cell lines. Microglial cells were the only cell type that constitutively expressed C1q. The ability of C1q to reassociate with newly formed C1r and C1s upon activation of C1 and subsequent inactivation by C1-Inh, may enable ongoing complement activation at sites of amyloid deposition, especially when C1-Inh is consumed and not replaced.

Aged↗
PubMed1999

The importance of inflammatory mechanisms for the development of Alzheimer's disease.

A variety of inflammatory proteins has been identified in brains of patients with Alzheimer's disease. The current data suggest that the inflammatory processes are intimately involved in several crucial events in the pathological cascade. Immunohistochemical studies reveal that those parts of the brain wherein the amyloid-beta deposits are closely associated with a chronic inflammatory response are strongly related to the characteristic symptoms. An inflammation-based approach could also provide a valuable theoretical framework to study the influence of extracerebral factors (such as acute phase reactants) on the clinical course of Alzheimer's disease.

Acute-Phase Reaction↗