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H M Schipper

Publications and source records attributed to H M Schipper.

At least 19 recordsLinked to original sources
PubMed2001

Assessment of suspected dementia.

At the Second Canadian Consensus Conference on Dementia (CCCD) (February, 1998), a group of neurologists, geriatricians, and psychiatrists met to consider guidelines for evaluation of dementia in Canada. This review paper formed a background paper for their discussion of dementia diagnosis. These experts from across the country concluded that diagnosis of suspected dementia cases continued to rest on skilled clinical assessment. Mental status exam, preferably in some quantifiable form, has become an essential part of the assessment. Selected laboratory tests are advisable in all cases (CBC, TSH, electrolytes, calcium, and glucose), but the CCCD continued to advise that CT scanning was mandatory only in selected cases where clinical findings pointed to another possibility besides Alzheimer's disease. The growing list of other diagnostic measures with potential usefulness in diagnosis of Alzheimer's disease or dementia in general was reviewed, but the evidence was judged as insufficient to support routine use of these tests by physicians. As new treatments for Alzheimer's disease become available, neurologists face new diagnostic challenges--differentiating Mild Cognitive Impairment, Frontotemporal dementias and Mixed dementias, and Lewy Body Dementia. Guidelines to aid in differential diagnosis are presented.

Aged↗
PubMed2001

Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis.

Proinflammatory cytokines, pathological iron deposition, and oxidative stress have been implicated in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). HO-1 mRNA levels and mitochondrial uptake of [(55)Fe]Cl(3)-derived iron were measured in rat astroglial cultures exposed to interleukin-1beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha) alone or in combination with the heme oxygenase-1 (HO-1) inhibitors, tin mesoporphyrin (SnMP) or dexamthasone (DEX), or interferon beta1b (INF-beta). HO-1 expression in astrocytes was evaluated by immunohistochemical staining of spinal cord tissue derived from MS and control subjects. IL-1beta or TNF-alpha promoted sequestration of non-transferrin-derived (55)Fe by astroglial mitochondria. HO-1 inhibitors, mitochondrial permeability transition pore (MTP) blockers and antioxidants significantly attenuated cytokine-related mitochondrial iron sequestration in these cells. IFN-beta decreased HO-1 expression and mitochondrial iron sequestration in IL-1beta- and TNF-alpha-challenged astroglia. The percentage of astrocytes coexpressing HO-1 in affected spinal cord from MS patients (57.3% +/- 12.8%) was significantly greater (p < 0.05) than in normal spinal cord derived from controls subjects (15.4% +/- 8.4%). HO-1 is over-expressed in MS spinal cord astroglia and may promote mitochondrial iron deposition in MS plaques. In MS, IFN-beta may attenuate glial HO-1 gene induction and aberrant mitochondrial iron deposition accruing from exposure to proinflammatory cytokines.

Animals↗
PubMed2000

Evaluation of heme oxygenase-1 as a systemic biological marker of sporadic AD.

BACKGROUND: Heme oxygenase-1 (HO-1) is a 32-kDa stress protein that catalyzes the degradation of heme to biliverdin. HO-1 immunoreactivity is greatly increased in neurons and astrocytes of the hippocampus and cerebral cortex of individuals with AD and colocalizes to senile plaques and neurofibrillary tangles. METHODS: We investigated whether systemic HO-1 regulation is also deranged in AD patients and whether blood HO-1 measurements provide a peripheral biomarker of the disease. Plasma HO-1 protein levels were measured by competitive ELISA and lymphocyte HO-1 mRNA levels were determined by Northern analysis in patients with early probable sporadic AD, normal elderly controls (NEC), normal younger controls, individuals with age-associated cognitive decline (AACD) not meeting AD criteria, and patients with non-Alzheimer dementia, nondementing neurologic illness, and chronic medical disorders. CSF HO-1 protein concentrations were also determined by ELISA in pathologically confirmed AD and control cases. RESULTS: Mean plasma HO-1 protein concentrations were significantly lower in AD patients (0.85 +/- 0.14 microg/mL) compared with NEC (1.77 +/- 0.34 microg/mL; p < 0.05) and control patients. The AACD group exhibited plasma HO-1 concentrations (1.06 +/- 0.33 microg/mL) intermediate between, but not different from, those of the AD patients and NEC. Lymphocyte HO-1 mRNA levels were lower in the AD cohort relative to NEC (p < 0.001) and individuals with AACD, non-Alzheimer dementia, nondementing neurologic illness, and chronic medical conditions. Lymphocyte HO-1 mRNA levels were also lower in the AACD group relative to NEC (p < 0.05). In comparison with all groups excluding AACD, the sensitivity and specificity of lymphocyte HO-1 mRNA measurement for diagnosis of early sporadic AD are 88% and 75%. Mean CSF HO-1 protein concentrations were lower (p < 0.01) in AD cases (19.07 ng/mL) relative to control values (32.48 ng/mL). CONCLUSIONS: Plasma and CSF HO-1 protein and lymphocyte HO-1 mRNA levels are decreased in subjects with sporadic AD. Quantitative assay for lymphocyte HO-1 mRNA expression may serve as a useful biologic marker in early sporadic AD.

Adult↗
PubMed2000

Cells containing immunoreactive estrogen receptor-alpha in the human basal forebrain.

The distribution of estrogen receptor protein-alpha (ER-alpha)-containing cells in the human hypothalamus and adjacent regions was studied using a monoclonal antibody (H222) raised against ER-alpha derived from MCF-7 human breast cancer cells. Reaction product was found in restricted populations of neurons and astrocyte-like cells. Neurons immunoreactive for ER-alpha were diffusely distributed within the basal forebrain and preoptic area, infundibular region, central hypothalamus, basal ganglia and amygdala. Immunoreactive astrocyte-like cells were noted within specific brain regions, including the lamina terminalis and subependymal peri-third-ventricular region. These data are consistent with the location of estrogen receptors in the basal forebrain of other species and the known effects of estrogens on the cellular functions of both neurons and supporting elements within the human hypothalamus and basal forebrain.

Amygdala↗
PubMed2000

Role of heme oxygenase-1 in the regulation of manganese superoxide dismutase gene expression in oxidatively-challenged astroglia.

Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme that reduces superoxide anion to hydrogen peroxide in cell mitochondria. MnSOD is overexpressed in normal aging brain and in various central nervous system disorders; however, the mechanisms mediating the upregulation of MnSOD under these conditions remain poorly understood. We previously reported that cysteamine (CSH) and other pro-oxidants rapidly induce the heme oxygenase-1 (HO-1) gene in cultured rat astroglia followed by late upregulation of MnSOD in these cells. In the present study, we demonstrate that antecedent upregulation of HO-1 is necessary and sufficient for subsequent induction of the MnSOD gene in neonatal rat astroglia challenged with CSH or dopamine, and in astroglial cultures transiently transfected with full-length human HO-1 cDNA. Treatment with potent antioxidants attenuates MnSOD expression in HO-1-transfected astroglia, strongly suggesting that intracellular oxidative stress signals MnSOD gene induction in these cells. Activation of this HO-1-MnSOD axis may play an important role in the pathogenesis of Alzheimer disease, Parkinson disease and other free radical-related neurodegenerative disorders. In these conditions, compensatory upregulation of MnSOD may protect mitochondria from oxidative damage accruing from heme-derived free iron and carbon monoxide liberated by the activity of HO-1.

Animals↗
PubMed2000

Heme oxygenase-1: role in brain aging and neurodegeneration.

The mechanisms responsible for excessive iron deposition and mitochondrial insufficiency in the aging and degenerating nervous system remain poorly understood. Heme oxygenase-1 (HO-1) is a 32kDa stress protein that degrades heme to biliverdin, free iron and carbon monoxide. Our laboratory has shown that cysteamine, dopamine, beta-amyloid, IL-1beta and TNF-alpha up-regulate HO-1 followed by mitochondrial sequestration of non-transferrin-derived 55Fe in cultured rat astroglia. In these cells and in rat astroglia transfected with the human HO-1 gene, mitochondrial iron trapping is abrogated by the HO-1 inhibitors, tin-mesoporphyrin and dexamethasone. We determined that HO-1 immunoreactivity is enhanced greatly in neurons and astrocytes of the hippocampus and cerebral cortex of Alzheimer subjects and co-localizes to senile plaques and neurofibrillary tangles (NFT). HO-1 staining is also augmented in astrocytes and decorates neuronal Lewy bodies in the Parkinson nigra. Collectively, our findings suggest that HO-1 over-expression contributes to the pathological iron deposition and mitochondrial damage documented in these aging-related neurodegenerative disorders. We recently observed that, paradoxically, HO-1 mRNA levels are markedly suppressed in peripheral lymphocytes of patients with early sporadic Alzheimer disease and may thus provide a useful biological marker of this condition.

Aging↗
PubMed2000

Increased T-type Ca2+ channel activity as a determinant of cellular toxicity in neuronal cell lines expressing polyglutamine-expanded human androgen receptors.

We have analyzed Ca2+ currents in two neuroblastoma-motor neuron hybrid cell lines that expressed normal or glutamine-expanded human androgen receptors (polyGln-expanded AR) either transiently or stably. The cell lines express a unique, low-threshold, transient type of Ca2+ current that is not affected by L-type Ca2+ channel blocker (PN 200-110), N-type Ca2+ channel blocker (omega-conotoxin GVIA) or P-type Ca2+ channel blocker (Agatoxin IVA) but is blocked by either Cd2+ or Ni2+. This pharmacological profile most closely resembles that of T-type Ca2+ channels [1-3]. Exposure to androgen had no effect on control cell lines or cells transfected with normal AR but significantly changed the steady-state activation in cells transfected with expanded AR. The observed negative shift in steady-state activation results in a large increase in the T-type Ca2+ channel window current. We suggest that Ca2+ overload due to abnormal voltage-dependence of transient Ca2+ channel activation may contribute to motor neuron toxicity in spinobulbar muscular atrophy (SBMA). This hypothesis is supported by the additional finding that, at concentrations that selectively block T-type Ca2+ channel currents, Ni2+ significantly reduced cell death in cell lines transfected with polyGln-expanded AR.

Calcium Channel Blockers↗
PubMed2000

Characterization of cis-acting elements in the promoter of the mouse metallothionein-3 gene. Activation of gene expression during neuronal differentiation of P19 embryonal carcinoma cells.

The metallothionein (MT)3 gene is expressed predominantly in the brain and the organs of the reproductive system, and fails to respond to metal ions in vivo. A CTG repeat was proposed to function as a potential repressor element in nonpermissive cells, and a sequence similar to the JC virus silencer element was found to function as a negative element in permissive primary astrocytes. The objective of this study was to characterize further the mechanisms governing cell-type specific MT-3 gene transcription. We searched for a suitable cell line expressing the MT-3 gene to be used for determination of MT-3 promoter tissue specificity, and showed that MT-3 expression is activated during neuroectodermal differentiation of P19 cells induced by retinoic acid to levels similar to those found in whole brain. Deletion of the CTG repeat or of the JC virus silencer did not promote MT-3 promoter activity in nonpermissive cells, or enhance expression in permissive cells. We identified MT-3 promoter sequences interacting with liver and brain nuclear proteins, as assayed by DNase I footprinting analyses and electrophoretic mobility shift assay, and assessed the role of these sequences in the regulation of MT-3 expression by cotransfection experiments. We generated stable transfectants in permissive C6 and nonpermissive NIH-3T3 cells, and analysed the methylation status of the MT-3 gene. These studies show that regulation of tissue-specific MT-3 gene expression does not appear to involve a repressor, and suggest that other mechanisms such as chromatin organization and epigenetic modifications could account for the absence of MT-3 gene transcription in nonpermissive cells.

3T3 Cells↗
PubMed2000

Heme oxygenase-1 induction and mitochondrial iron sequestration in astroglia exposed to amyloid peptides.

The mechanisms responsible for pathological iron deposition and mitochondrial insufficiency that have been documented in the brains of Alzheimer (AD) patients remain poorly understood. In the present study, we demonstrate that low-micromolar concentrations of amyloid1-40 (A40) and amyloid 1-42 (A42), peptides implicated in the pathogenesis of AD, increase levels of heme oxygenase-1 (HO-1) mRNA and protein in cultured rat astroglia. Furthermore, 6 days of exposure to amyloid augments the sequestration of 55FeCl3-derived iron by astroglial mitochondria without affecting the disposition of this metal in whole-cell and lysosomal compartments. Mitochondrial iron deposition was not observed in the amyloid-treated glia when diferric-transferrin served as the metal donor. We had previously shown that inhibitors of HO-1 and the mitochondrial permeability transition pore (MTP) block the uptake of mitochondrial iron in astrocytes exposed to the pro-oxidant effects of dopamine and several pro-inflammatory cytokines. Similarly, in the current study, amyloid-induced mitochondrial iron trapping was significantly attenuated by co-administration of the HO-1 transcriptional suppressor, dexamethasone (DEX) or the MTP blocker, cyclosporin A (CSA). Thus, the marked enhancement of HO-1 expression previously demonstrated in AD-affected neurons and astroglia may transduce amyloid (oxidative) stress into the abnormal patterns of iron deposition and mitochondrial insufficiency characteristic of this disease. Finally, in experiments employing cytotoxic concentrations of A40, we provide evidence that inhibition of HO-1 transcription and related mitochondrial iron deposition may be an important mechanism by which DEX protects tissues subjected to amyloid stress.

Amyloid beta-Peptides↗
PubMed1999

Cysteamine pretreatment of the astroglial substratum (mitochondrial iron sequestration) enhances PC12 cell vulnerability to oxidative injury.

Much of the excess iron reported in the substantia nigra of subjects with Parkinson's disease (PD) implicates nonneuronal (glial) cellular compartments. Yet, the significance of these glial iron deposits vis-a-vis toxicity to indigent nigrostriatal dopaminergic neurons remains unclear. Cysteamine (CSH) induces the appearance of iron-rich (peroxidase-positive) cytoplasmic inclusions in cultured rat astroglia, which are identical to glial inclusions that progressively accumulate in substantia nigra and other subcortical brain regions with advancing age. We previously demonstrated that the iron-mediated peroxidase activity in these cells oxidizes dopamine and other catechols to potentially neurotoxic semiquinone radicals. In the present study, we cocultured catecholamine-secreting PC12 cells (as low-density dispersed cells or high-density colonies) atop monolayers of either CSH-pretreated (iron-enriched) or control rat astroglial substrata. In some experiments, the PC12 cells were differentiated with nerve growth factor (NGF). The nature of the glial substratum did not appreciably affect the growth characteristics of the PC12 cells. However, undifferentiated PC12 cells grown atop CSH-pretreated astrocytes (a senescent glial phenotype) were far more susceptible to dopamine(1 microM)-H2O2(1 microM)-related killing than PC12 cells cultured on control astroglia. Differentiated PC12 cells behaved similarly although the fraction killed was about half that seen with the undifferentiated PC12 cells. In the latter experiments, PC12 cell death was abrogated by coadministration of the antioxidants, ascorbate (200 microM), melatonin (100 microM), or resveratrol (50 microM) or the iron chelator, deferoxamine (400 microM), attesting to the role of oxidative stress and catalytic iron in the mechanism of PC12 cell death in this system. The aging-associated accumulation of redox-active iron in subcortical astrocytes may facilitate the bioactivation of dopamine to neuronotoxic free radical intermediates and thereby predispose the senescent nervous system to PD and other neurodegenerative disorders.

Animals↗
PubMed1999

Acceleration of ageing-related gliopathic changes and hippocampal dysfunction following intracerebroventricular infusion of cysteamine in adult rats.

The sulphydryl agent, cysteamine, accelerates the ageing-related accumulation of peroxidase-positive (iron-rich) cytoplasmic inclusions in rat subcortical astroglia and induces their appearance in primary neuroglial cultures. In the present study, infusion of cysteamine into the lateral ventricle of young, adult rats (1 mg/day for three weeks followed by a one-month drug "washout" period) significantly increased numbers of peroxidase-positive astrocytic granules in the stratum oriens of the CA1 hippocampus relative to saline-infused controls. In contrast to the gliopathic changes, no evidence of neuronal or myelin damage was observed in the cysteamine-exposed rats. The cysteamine-treated animals exhibited significant impairment in spatial learning as determined using a three-panel runway task. The working memory deficits were more robust at the end of the drug washout period than immediately following cessation of the cysteamine infusion. Thus, the cysteamine-related memory deficits are of long duration and are not due to any acute neuroactive properties of the drug itself. Using hippocampal slices prepared after the drug washout period, we observed attenuated paired-pulse depression, with no significant effects on basal excitatory synaptic transmission or induction of long-term potentiation, in the cysteamine-infused animals relative to controls. We propose that, in cysteamine-treated rats and in the course of normal ageing, hippocampal dysfunction and associated cognitive deficits may be secondary to fundamental pathological processes originating within the astroglial compartment.

Aging↗
PubMed1999

The topography and subcellular distribution of mitogen-activated protein kinase kinase1 (MEK1) in adult rat brain and differentiating PC12 cells.

Mitogen-activated protein kinase signal transduction pathway involved in the regulation of proliferation and differentiation of various mammalian cells consists of a sequential activation of three protein kinases, Raf, mitogen-activated protein kinase kinase, and mitogen-activated protein kinase. These kinases are highly expressed in brain and play an important role in neuronal signalling. In this study, to further characterize mitogen-activated protein kinase signalling pathway in brain, we have elucidated the topography and subcellular distribution of mitogen-activated protein kinase kinasel in adult rat brain and differentiating PC12 cells. Our immunohistochemical data indicate that mitogen-activated protein kinase kinase1 is widely distributed throughout the brain and expressed prominently in cortex, hippocampus, brainstem, hypothalamus and cerebellum. In these areas of brain mitogen-activated protein kinase kinasel is exclusively neuronal in origin and is localized within perikarya and dendrites. Confocal microscopy data has determined that a portion of mitogen-activated protein kinase kinase1 in rat brain is co-localized with microtubules. This co-localization was observed only within neuritic shaft and cilia of ventricular ependymal cells. In nerve growth factor-induced differentiating PC12 cells, mitogen-activated protein kinase kinase1 displays co-localization with microtubules within proximal regions of neuritic shafts and their junctions with the cell somas. From bovine brain extract, mitogen-activated protein kinase kinasel co-purifies with microtubules. In vitro kinase assay detected mitogen-activated protein kinase kinase1 activity within purified microtubules. These observations indicate that mitogen-activated protein kinase kinase1 is associated with microtubules within some specialized compartments of the brain and microtubule-associated mitogen-activated protein kinase kinase1 is catalytically active.

Animals↗
PubMed1999

Mitochondrial iron sequestration in dopamine-challenged astroglia: role of heme oxygenase-1 and the permeability transition pore.

Little is currently known concerning the mechanisms responsible for the excessive deposition of redox-active iron in the substantia nigra of subjects with Parkinson's disease (PD). In the present study, we demonstrate that dopamine promotes the selective sequestration of non-transferrin-derived iron by the mitochondrial compartment of cultured rat astroglia and that the mechanism underlying this novel dopamine effect is oxidative in nature. We also provide evidence that up-regulation of the stress protein heme oxygenase-1 (HO-1) is both necessary and sufficient for mitochondrial iron trapping in dopamine-challenged astroglia. Finally, we show that opening of the mitochondrial transition pore (MTP) mediates the influx of non-transferrin-derived iron into mitochondria of dopamine-stimulated and HO-1-transfected astroglia. Our findings provide an explanation for the pathological iron sequestration, mitochondrial insufficiency, and amplification of oxidative injury reported in the brains of PD subjects. Pharmacological blockade of transition metal trapping by "stressed" astroglial mitochondria (e.g., using HO-1 inhibitors or modulators of the MTP) may afford effective neuroprotection in patients with PD and other neurological afflictions.

Animals↗
PubMed1998

Experimental induction of corpora amylacea in adult rat brain.

Corpora amylacea (CA) are glycoproteinaceous inclusions that accumulate in astroglia and other brain cells as a function of advancing age and, to an even greater extent, in several human neurodegenerative conditions. The mechanisms responsible for their biogenesis and their subcellular origin(s) remain unclear. We previously demonstrated that the sulfhydryl agent, cysteamine (CSH), promotes the accumulation of CA-like inclusions in cultured rat astroglia. In the present study, we show that subcutaneous administration of CSH to adult rats (150 mg/kg for 6 weeks followed by a 5-week drug-washout period) elicits the accumulation of CA in many cortical and subcortical brain regions. As in the aging human brain and in CSH-treated rat astrocyte cultures, the inclusions are periodic acid-Schiff -positive and are consistently immunostained with antibodies directed against mitochondrial epitopes and ubiquitin. Our findings support our contention that mitochondria are important structural precursors of CA, and that CSH accelerates aging-like processes in rat astroglia both in vitro and in the intact brain.

Aging↗
PubMed1998

Hepatocyte growth factor (HGF/SF) in Alzheimer's disease.

Hepatocyte growth factor (HGF/SF), is a heparin-binding polypeptide which stimulates DNA synthesis in a variety of cell types and also promotes cell migration and morphogenesis. HGF/SF mRNA has been found in a variety of tissues, including brain. In a previous study, we showed that basic fibroblast growth factor (bFGF), another heparin-binding protein is increased in Alzheimer's disease (AD), and appears to be associated with the heparan-sulfate proteoglycans bound to B/A4 amyloid (Biochem. Biophys. Res. Commun. 171 (1990) 690-696). In the present study, we examined the distribution of HGF/SF in 4% paraformaldehyde fixed samples of prefrontal cortex from control and Alzheimer patients, in order to assess the possibility that HGF/SF may be found in association with the pathologic changes which occur in Alzheimer's disease. A specific polyclonal antibody directed against HGF/SF revealed widespread HGF/SF-like immunoreactivity in both the cerebral cortex and white matter. Confocal microscopy confirmed that HGF/SF could be found in both GFAP positive astrocytes and LN3 positive microglia cells, as well as rare scattered cortical neurons. In the AD cases studied, the immunoreactivity was increased within both the astrocytes and microglial cells surrounding individual senile plaques. No staining was seen within the neurofibrillary tangles. Western blot analysis confirmed the normal molecular form of HGF/SF in Alzheimer's disease. Quantitative ELISA assay demonstrated a significant increase in HGF/SF in AD relative to age matched controls. These studies confirm the presence of HGF/SF immunoreactivity within neurons, astrocytes and microglial cells. They also indicate that HGF/SF may be increased within senile plaques as a function of the gliosis and microglial proliferation which occurs in association with these structures in Alzheimer's disease.

Aged↗
PubMed1998

Neural heme oxygenase-1 expression in idiopathic Parkinson's disease.

Heme oxygenase-1 is a cellular stress protein expressed in brain and other tissues in response to oxidative challenge and other noxious stimuli. In the present study, immunohistochemistry was used to assess HO-1 expression in various postmortem human brain specimens derived from PD and control subjects. In the substantia nigra of both PD and control specimens, moderate HO-1 immunoreactivity was consistently observed in neuromelanin-containing (dopaminergic) neurons. Lewy bodies in PD nigra neurons exhibited intense HO-1 immunostaining in their peripheries. In both PD and control specimens, neuronal HO-1 staining was faint or nondetectable in the other brain regions surveyed. The fraction of GFAP-positive astroglia expressing HO-1 in PD substantia nigra (77.1 +/- 12.3) was significantly greater than that observed in the substantia nigra of control subjects (18.7 +/- 7.1; P = 0.0015). In the other regions examined, percentages of GFAP-positive astroglia coexpressing HO-1 were relatively low and did not differ significantly (P > 0.05) between control and PD specimens. Upregulation of HO-1 in the substantia nigra of PD subjects supports the view that the affected tissue is experiencing chronic oxidative stress. In addition, excessive cellular levels of heme-derived free iron and carbon monoxide resulting from HO-1 overactivity may contribute to the pathogenesis of PD.

Aged↗