Biomedical subjects

Rivka Ravid

Publications and source records attributed to Rivka Ravid.

At least 37 records · Page 2Linked to original sources

PubMed2005

Cultured human adult microglia from different donors display stable cytokine, chemokine and growth factor gene profiles but respond differently to a pro-inflammatory stimulus.

OBJECTIVES: Brain microglia are highly responsive cells in the central nervous system that exert key functions in host defense as well as in neuroprotection and regeneration. In this study the gene expression profiles for 268 cytokines, chemokines, growth factors and their receptors were examined in cultures of purified human adult microglia, using cDNA array profiling. METHODS: Microglia from 9 different donors were compared, also following challenge of such microglia with the pro-inflammatory cytokines TNF-alpha and IFN-gamma. RESULTS: A stable pattern was observed of genes abundantly expressed in the different cultures under standard conditions. Genes abundantly expressed in all microglia cultures include CCL2 (MCP-1), thymosin beta-10, migration-inhibitory factor-related protein 8 (MRP8), MRP14, corticotropin-releasing factor receptor 1 and endothelin 2. Abundant gene products novel to microglia were neuromodulin (GAP43) and Flt3 ligand. Yet, treatment with TNF-alpha and IFN-gamma led to widely different response profiles among the different cultures. CONCLUSION: These data show a surprising level of heterogeneity among human adult microglia cultures in their response to a pro-inflammatory stimulus despite the standardized methodology to examine this response.

Aged↗

PubMed2005

Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by beta-amyloid (A beta) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5' region of CH25H revealed three common haplotypes, CH25Hchi2, CH25Hchi3 and CH25Hchi4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hchi4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain A beta deposits in carriers of CH25Hchi4 and CH25Hchi3 haplotypes, whereas no A beta deposits were present in CH25Hchi2 carriers. Together, these results are compatible with a role of CH25Hchi4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain A beta deposition.

5' Untranslated Regions↗

PubMed2004

The spinal cord in multiple sclerosis: relationship of high-spatial-resolution quantitative MR imaging findings to histopathologic results.

PURPOSE: To correlate quantitative magnetic resonance (MR) imaging data (ie, relaxation times and magnetization transfer ratios [MTRs]) with histopathologic findings of demyelination and axonal disease in cervical spinal cord specimens from patients with multiple sclerosis (MS) and control subjects. MATERIALS AND METHODS: Formaldehyde-fixed cervical spinal cord specimens from 11 patients with MS-three men and eight women (mean age at death, 66 years +/- 11.3 [standard deviation])-and two female control subjects without neurologic disease (83 and 41 years of age at death) were examined at 4.7 T. Relaxation time measurements and MTR mapping were performed. Analyses included the whole cord area and region-of-interest measurements. Histopathologic analyses included semiquantitative myelin and quantitative axonal analysis. RESULTS: Compared with control specimens (P < .001, analysis of variance), specimens from patients with MS had smaller cord areas (mean area, 59.0 mm(2) +/- 12.5 vs 72.7 mm(2) +/- 10.0), significant prolongation of T1 (mean prolongation, 30%) and T2 (mean prolongation, 13%), and decreased MTRs (mean, 10.5%). Within MS specimens, 58% of the white matter area displayed signal intensity abnormalities on intermediate-weighted MR images. The number of axons in normal-appearing white matter in MS specimens was, on average, 46% lower than the number of axons in white matter in control specimens. All quantitative MR parameters correlated well with demyelination; the correlation with T2 relaxation time was the strongest (r = 0.77, Spearman and Kendall nonparametric correlations). By contrast, quantitative MR parameters correlated less well with axonal density; the correlation with T2 relaxation time was the strongest (r = -0.44, Spearman and Kendall nonparametric correlations). Multilevel analysis, corrected for age and MS phenotype, could not result in a model explaining axonal density on the basis of quantitative MR parameters when myelin density was included as a predictor. CONCLUSION: Changes in quantitative MR imaging parameters in the cervical spinal cord in MS are mainly determined by demyelination and do not reflect axonal disease well.

Adult↗

PubMed2004

Akt activity in Alzheimer's disease and other neurodegenerative disorders.

Enzyme activities of the serine/threonine kinase Akt were compared in mid-temporal and mid-frontal cortices from Alzheimer's disease cases and matched controls. Activities (GSK-3alpha/beta fusion protein phosphorylation by immunoprecipitated Akt) were significantly increased in temporal cortex soluble fractions from Alzheimer's disease compared with non-disease controls and positive disease controls with another neurodegenerative disease. Temporal cortex soluble fraction Akt activities positively correlated with Braak staging for neurofibrillary changes. Frontal cortex soluble fraction activities were significantly reduced in positive disease compared with Alzheimer's disease cases and non-disease controls. Strong Ser Akt immunoreactivity was seen in Alzheimer's disease pyramidal neurons likely undergoing degeneration and in reactive astroglia. Non-disease and positive disease controls showed moderate Ser Akt immunostaining of occasional pyramidal neurons.

Aged↗

PubMed2004

EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries.

1. Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E(2) (PGE(2)) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries in vitro. 2. In the presence of indomethacin (3 microm) and the TP receptor antagonist GR32191 (1 microM), PGE(2) was found to relax phenylephrine precontracted cerebral arterial rings in a concentration-dependent manner (mean pEC(50) 8.0+/-0.1, n=5). 3. Establishment of a rank order of potency using the EP(4)>EP(2) agonist 11-deoxy PGE(1), and the EP(2)>EP(4) agonist PGE(1)-OH (mean pEC(50) of 7.6+/-0.1 (n=6) and 6.4+/-0.1 (n=4), respectively), suggested the presence of functional EP(4) receptors. Furthermore, the selective EP(2) receptor agonist butaprost at concentrations <1 microM failed to relax the tissues. 4. Blockade of EP(4) receptors with the EP(4) receptor antagonists AH23848 and EP(4)A caused significant rightward displacements in PGE(2) concentration-response curves, exhibiting pA(2) and pK(B) values of 5.7+/-0.1, n=3, and 8.4, n=3, respectively. 5. The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC(50) values 8.3+/-0.1 (n=4) and 8.1+/-0.1 (n=9), respectively). In contrast, the DP and FP receptor agonists PGD(2) and PGF(2 alpha) failed to cause appreciable relaxation or contraction at concentrations of up to 30 microm. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration-dependent contraction of cerebral artery (mean pEC(50) 7.4+/-0.3, n=3). 6. These data demonstrate the presence of prostanoid EP(4) receptors mediating PGE(2) vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2004

DJ-1 colocalizes with tau inclusions: a link between parkinsonism and dementia.

Two novel mutations recently have been identified in the DJ-1 gene that cause a new form of autosomal recessive, early-onset parkinsonism. Because the pathological role of this protein is unknown, we examined the issue here and report the colocalization of DJ-1 protein within a subset of pathological tau inclusions in a diverse group of neurodegenerative disorders known as tauopathies. Our study extends the view that different neurodegenerative diseases may have similar pathological mechanisms, and that these processes likely include DJ-1.

Aged↗

PubMed2004

Expression of CCR7 in multiple sclerosis: implications for CNS immunity.

It is unclear how immune cells traffic between the lymphoid compartment and the central nervous system (CNS), which lacks lymphatic vessels and is shielded by the blood-brain barrier. We studied the expression of CCR7, a chemokine receptor required for migration of T cells and dendritic cells (DCs) to lymphoid organs, in the CNS of patients with multiple sclerosis (MS) to gain insight into pathways for CNS immune cell trafficking. Inflamed MS lesions contained numerous CCR7+ myeloid cells expressing major histocompatibility complex class II, CD68 and CD86, consistent with maturing DCs. CCR7+ DCs also were identified in cerebrospinal fluid (CSF). These observations suggested that the afferent limb of CNS immunity is comprised, in part, of DCs, which are generated within the CNS and migrate to deep cervical lymph nodes through the CSF after antigen capture. Ninety percent of CSF T cells expressed CCR7 and CSF from patients with MS was relatively depleted of CCR7-negative effector-memory T cells. In contrast, all T cells in parenchymal MS lesions lacked CCR7, indicating local retention and differentiation of central-memory T cells upon restimulation by antigen within the CNS. These data suggested that the efferent limb of CNS immunity is executed by central-memory T cells, which enter CSF directly from the circulation.

Adolescent↗

PubMed2004

Colocalization and alteration of estrogen receptor-alpha and -beta in the hippocampus in Alzheimer's disease.

The human hippocampus is severely affected in Alzheimer's disease (AD). Because postmenopausal estrogen use may decrease the risk and delay the onset and progression of AD, possibly by a direct action on the hippocampal neurons, we used fluorescence immunocytochemistry to examine the colocalization of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) in the hippocampus of elderly human controls and AD patients. Double-labeling cells (DLCs) of ERalpha and ERbeta can be divided into 3 types: double-cytoplasm-staining cells (DCCs), double-nucleus-staining cells (DNCs), and ERalpha nucleus-staining and ERbeta cytoplasm-staining cells (NCCs). There was no difference in the percentage of DLCs in total ERalpha-positive cells or in total ERbeta-positive cells in the CA1 to CA4 subfields of the hippocampus between controls and AD patients. Interestingly, the ratio of DNCs to the total ERalpha-positive cells (2.6% +/- 0.5%) or to the total ERbeta-positive cells (1.8% +/- 0.3%) in the CA1 subfield of the AD hippocampus was significantly decreased in comparison with controls (5.0% +/- 0.7% and 3.9% +/- 0.6%, respectively; P<0.001), suggesting that changes in the compartmentalization of these receptors could play a role in the pathogenesis of AD.

Aged↗

PubMed2004

Multiple sclerosis as a generalized CNS disease--comparative microarray analysis of normal appearing white matter and lesions in secondary progressive MS.

We used microarrays to compare the gene expression profile in active lesions and donor-matched normal appearing white matter (NAWM) from brain autopsy samples of patients with secondary progressive multiple sclerosis (MS) with that from controls who died from non-neurological diseases. The 123 genes in lesions, and 47 genes in NAWM(MS) were differentially expressed. Lesions distinguished from NAWM(MS) by a higher expression of genes related to immunoglobulin synthesis and neuroglial differentiation, while cellular immune response elements were equally dysregulated in both tissue compartments. Current results provide molecular evidence of a continuum of dysfunctional homeostasis and inflammatory changes between lesions and NAWM(MS), and support the concept of MS pathogenesis being a generalised process that involves the entire CNS.

Brain↗

PubMed2004

Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17.

Hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in the tau gene shows a wide range in age at onset, several distinct clinical presentations, and a spectrum of tau pathology. Although the clinical and pathological phenotype often correlate with the location of the mutation, there also exists considerable interfamilial and intrafamilial phenotypical variation. Not all families with FTDP-17 do have mutations and deposition of hyperphosphorylated tau in the brain, but show ubiquitin-positive, tau-negative inclusions. Future research should focus on the role of other genetic and environmental factors in this form of FTDP-17, whereas the responsible gene defect(s) has still to be identified for hereditary FTD without tau mutations.

Chromosomes, Human, Pair 17↗

PubMed2004

First evidence for helical transitions in supercoiled DNA by amyloid Beta Peptide (1-42) and aluminum: a new insight in understanding Alzheimer's disease.

Previously, we evidenced a B --> Z helical change in Alzheimer's brain genomic DNA, leading to a hypothesis that Alzheimer's disease (AD) etiological factors such as aluminum (Al), amyloid beta (Abeta) peptide, and Tau might play a role in modulating DNA topology. In the present study, we investigated the interaction of Al and Abeta with DNA. Our results show that Abeta(1-42) could induce a B --> Psi (Psi) conformational change in pUC 18 supercoiled DNA (scDNA), Abeta(1-16) caused an altered B-form, whereas Al induced a complex B-C-A mixed conformation. Ethidium bromide binding and agarose gel electrophoresis studies revealed that Al uncoiled the DNAto a fully relaxed form, whereas Abeta(1-42) and Abeta(1-16) effected a partial uncoiling and also showed differential sensitivity toward chloroquine-induced topoisomer separation. Our findings show for the first time that Abeta and Al modulate both helicity and superhelicity in scDNA. A new hypothetical model explaining the potential toxicity of Abeta and Al in terms of their DNA binding properties leading to DNA conformational alteration is proposed.

Aged↗

PubMed2003

Estrogen receptors and metabolic activity in the human tuberomamillary nucleus: changes in relation to sex, aging and Alzheimer's disease.

The human tuberomamillary nucleus (TMN), that is the sole source of histamine in the brain, is involved in arousal, learning and memory and is impaired in Alzheimer's disease (AD) as shown by the presence of cytoskeletal alterations, a reduction in the number of large neurons, a diminished neuronal metabolic activity and decreased histamine levels in the hypothalamus and cortex. Experimental data and the presence of sex hormone receptors suggest an important role of sex steroids in the regulation of the function of TMN neurons. Therefore, we investigated sex-, age- and Alzheimer-related changes in estrogen receptor alpha and beta (ERalpha and ERbeta) in the TMN. In addition, metabolic activity changes of TMN neurons were determined by measuring Golgi apparatus (GA) and cell size. In the present study, ERalpha immunocytochemical expression in AD patients did not differ from that in elderly controls. However, a larger amount of cytoplasmic ERbeta was found in the TMN cells of AD patients. Earlier studies, using the GA size as a parameter, have shown a clearly decreased metabolic activity in the TMN neurons in AD. In the present study, the size of the GA did not change during aging, indicating the absence of strong metabolic changes. Cell size of the TMN neurons appeared to increase during normal aging in men but not in women. Concluding, the enhanced cytoplasmic expression of ERbeta in the TMN may be involved in the diminished neuronal metabolism of these neurons in AD patients.

Adult↗

PubMed2003

Very low levels of the glucocorticoid receptor beta isoform in the human hippocampus as shown by Taqman RT-PCR and immunocytochemistry.

The hippocampus is an important target for glucocorticoid hormones. Glucocorticoid receptor (GR) mediated feedback in this area is important for control of behavioural adaptation. An alternative splice variant, the GRbeta (GRbeta) isoform, does not bind ligand and has been proposed to inhibit classic GRalpha-mediated transactivation of target genes. Hence, an increased ratio of GRbeta to GRalpha may induce relative corticosteroid-resistance, as e.g. presumed to occur in major depression. To investigate whether GRbeta is involved in the human hippocampus, we studied GRalpha and GRbeta expression levels in postmortem hippocampal tissue of control subjects by quantitative PCR (Taqman RT-PCR) and immunocytochemistry. Taqman RT-PCR demonstrated a very low relative abundance of GRbeta in the human hippocampus (GRalpha:GRbeta ratio approximately 14,500:1). Immunohistochemical analysis confirmed the occurrence of isolated profiles indeed displaying nuclear staining in the main hippocampal subregions. Subsequent double immunofluorescent analysis revealed that >98% of these GRbeta positive cells were double positive for leucocyte common antigen, that identifies exclusively blood-derived cells of haematopoietic origin, including microglia. We conclude that GRbeta is present in very low amounts in the control human hippocampus, and that of these low numbers of cells, notably, almost all are derived from blood which is inevitably present in postmortem tissue. A functionally relevant role for the GRbeta in control of the human hippocampus is therefore not very likely. Whether this is altered in disease conditions awaits further research.

Aged↗

PubMed2003

Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study.

Since 1994, a population-based study of frontotemporal dementia (FTD) in The Netherlands has aimed to ascertain all patients with FTD, and first prevalence estimates based on 74 patients were reported in 1998. Here, we present new prevalence estimates after expansion of our FTD population to 245 patients, with emphasis on the prevalence in the province Zuid-Holland where the main study centre is located. All neurologists and physicians in nursing homes received a yearly postal enquiry about suspected FTD cases. FTD was diagnosed in 245 patients according to the Lund-Manchester criteria, supported by neuroimaging and neuropsychology. tau mutation analysis was performed in a subgroup of 154 patients (63%), and 40 out of 98 patients (41%) who died during follow-up were autopsied during the course of the study. The prevalence of FTD in the province Zuid-Holland was 3.6 per 100,000 at age 50-59 years, 9.4 per 100,000 at age 60-69 years and 3.8 per 100,000 at age 70-79 years. The median age at onset of the 245 patients (51% female) was 58.0 years (range 33-80 years). Dementia in one or more first-degree family members was found in 43% of patients and mutation analysis of the tau gene showed mutations in 34 patients (19 P301L, five L315R, four G272V, four R406W, one Delta K280 and one S320F), all with a positive family history for dementia (14% of the total population, 32% of patients with a positive family history). Pathological findings in the 40 autopsied patients consisted of dementia lacking distinctive histology in 22%, FTD with ubiquitin-positive inclusions in 33%, Pick's disease in 15% and tauopathy in the remaining 30% of patients, with tau mutations identified in more than half of the latter patients. We conclude that the prevalence of FTD in The Netherlands is higher than previously reported, confirming that FTD is more common than was previously thought. The finding of tau mutations in 32% of patients with a positive family history for dementia justifies mutation screening in FTD patients with a positive family history, while tau mutations in non-familiar cases are rare.

Adult↗

PubMed2003

Decreased estrogen receptor-alpha expression in hippocampal neurons in relation to hyperphosphorylated tau in Alzheimer patients.

Emerging evidence has demonstrated the neuroprotection of estrogen in Alzheimer's disease (AD). The hippocampus, an important target of estrogen action, is severely affected in the Alzheimer process. The aim of present study was to detect the distribution of estrogen receptor-alpha (ER-alpha) and the relationship between ER-alpha-containing neurons and the pretangles stained by Alz-50 in the hippocampus of AD patients. The results showed that more than half of hippocampal neurons expressed ER-alpha. The number of cytoplasmic ER-alpha-positive neurons was significantly decreased in the CA1 and CA2 subfields of AD hippocampus, but the ratio of these ER-alpha-expressing neurons to the nucleolated neuronal profiles stained by thionin was not different between the two groups. Interestingly, the number of nuclear ER-alpha-staining neurons was also markedly decreased in the CA1 and CA2 subfields of AD hippocampus, and the percentage of these nuclear staining neurons was also significantly decreased in the same subfields. Furthermore, some double-labeled neurons containing ER-alpha and Alz-50 were found in AD patients. However, in these double-labeled neurons, ER-alpha was only located in the cytoplasm. Thus, we hypothesize that the nuclear ER-alpha may play more important roles of neuroprotection during the process of AD.

Aged↗

PubMed2003

Correlation of oxidative stress and the loss of the nicotinic receptor alpha 4 subunit in the temporal cortex of patients with Alzheimer's disease.

The correlation between oxidative stress and the loss of nicotinic acetylcholine receptor (nAChR) alpha4 subunit has been investigated in the temporal cortex from patients with Alzheimer's disease (AD). The level of lipid peroxidation was significantly increased in AD brains, whereas there were no significant changes in protein oxidation either in whole tissues or the cellular membrane protein parts between AD brains and controls. The nAChR alpha4 subunit at protein level was significantly decreased in AD brains. Furthermore, there was a correlation between the increased levels of lipid peroxidation and the decreased numbers of the alpha4 subunit protein in AD brains. We suggest that lipid peroxidation might be a sensitive target in AD brain and related the mechanism of the loss of the nAChR alpha4 subunit in the disease.

Aged↗

PubMed2003

DC11: a novel monoclonal antibody revealing Alzheimer's disease-specific tau epitope.

Using tau protein extracts from Alzheimer's disease (AD) brain tissue, we generated a monoclonal antibody (mAb DC11) which decorated neurofibrillary pathology in brain derived from AD patients on immunohistochemistry, and which lacked reactivity with healthy brain tissue. The same pattern of DC11 specificity was observed on Western blot. The main constituent of structures decorated by DC11 is microtubule-associated protein tau. In Western blot, DC11 recognized neither native healthy tau nor its full length recombinant counterpart. However, the mAb showed strong immunoreactivity with truncated tau (residues tau151-421), thus indicating the requirement for a conformational epitope. Importantly, the DC11 epitope was phosphorylation independent. The immunochemical parameters of mAb show that DC11 could represent a novel structural probe with the specificity for conformation of pathological tau present in AD brains.

Aged↗

PubMed2003

Variable phenotypic expression and extensive tau pathology in two families with the novel tau mutation L315R.

Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe two Dutch families with familial frontotemporal dementia associated with the novel missense mutation L315R in exon 11 of tau. The age at onset of disease showed a large variation within each family, ranging from 25 to 64 years. Incomplete penetrance was established in an 82-year-old mutation carrier with no signs of dementia and appeared probable in two additional subjects. The brains of two affected subjects were studied and showed extensive tau pathology in neurons (Pick-like inclusions) and astroglial cells, particularly in the frontotemporal cortex and the hippocampal formation. Sarkosyl-insoluble tau extracted from the cerebral cortex showed the presence of straight and twisted tau filaments and a pattern of pathological tau bands similar to that of Pick's disease. Upon dephosphorylation, only five of the six brain tau isoforms were observed, with the shortest isoform being undetectable. All six tau isoforms were present in soluble brain tau. Recombinant tau proteins with the L315R mutation showed a reduced ability to promote microtubule assembly.

Adult↗