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Biomedical subjects

R Ravid

Publications and source records attributed to R Ravid.

At least 55 records · Page 3Linked to original sources
PubMed1997

Increased amount of zinc in the hippocampus and amygdala of Alzheimer's diseased brains: a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material.

Zinc has been implicated as a contributing cause of the neuropathology of Alzheimer's disease (AD), but consensus on the zinc content of AD brains has not yet been established. In the present study, multi-element PIXE was used to measure zinc in cryostat sections of brain tissue from AD patients and from normal control subjects. Compared to their age-matched controls, the AD patients showed an increase in zinc in the hippocampal and amygdalar regions. The instrumental PIXE assays do not show whether the zinc changes are due to altered zinc in the boutons of Zinc-ENriched (ZEN) neurons, i.e., zinc ions in synaptic vesicles, or to changes in the amount of zinc tightly bound to macromolecules. We hypothesise that the increased zinc level is caused by an increase in the amount of ZEN terminals. Such an increase could be the result of a sprout of ZEN terminals in diseased areas of the brain.

Aged↗
PubMed1997

Ethical aspects to be considered in brain banking.

A brain bank is a prospective source of adequately collected and preserved tissues of the central nervous system obtained via a donor program, which are supplied for neurobiological research. Brain tissue banks collect brains, serum and cerebro-spinal fluid from patients suffering from neurological disorders such as Alzheimer's diseases, Parkinson's disease and multiple sclerosis for diagnostic purposes and for the development of future diagnostic tests. To create and develop the right infrastructure underlying brain bank activities, one should have a medico-legal and ethical support according to local legislation. From an ethical point of view, brain bank activities can be divided into the following categories: a) factors related to the donor program; b) factors related to handling and management of organs; c) factors related to scientific research. The present paper deals with the above mentioned issues according to world-wide recognised ethical considerations and recommendations of several official statements, and specifies the objectives of the European Brain Bank Network (EBBN).

Adult↗
PubMed1996

Quantification of APP and APLP2 mRNA in APOE genotyped Alzheimer's disease brains.

Amyloid precursor protein (APP) is metabolised to produce A beta, a peptide found aggregated in Alzheimer's disease neuritic plaques. APP is a member of a multigene protein family which includes amyloid precursor-like protein 2 (APLP2). Since A beta accumulation can be triggered by factors acting up- or downstream of APP processing, we investigated whether APP mRNA expression was altered in Alzheimer's disease post-mortem cerebral cortex. In addition, we characterised cortical APLP2 mRNA levels. Quantitative RNA-RNA solution hybridisation-RNase protection was used to assay total APP. APP containing the Kunitz-type protease inhibitor (KPI) insert and APLP2 mRNA in mid-temporal and superior frontal cortices from apolipoprotein E-genotyped subjects with Alzheimer's disease, other neurological diseases and non-demented controls. Approximately 3 times more APP than APLP2 mRNA was detected and about 70% of total APP mRNA contained the KPI insert in the control subjects. Total APP and APLP2 mRNA levels were significantly reduced in Alzheimer's disease mid-temporal, but not superior frontal cortex, suggesting that regional reductions in these mRNA correlate with severity of disease pathology. A small significant increase in the proportion of APP KPI mRNA was seen in both cortical regions in Alzheimer's disease. Apolipoprotein E genotype did not influence cortical levels of total APP, APP KPI or APLP2 mRNA. Alzheimer's disease-related increases in tissue DNA content were seen in both regions studied, while tissue RNA levels were reduced in the positive disease controls. In summary, these results indicate that Alzheimer's disease is not associated with over-expression of either APP or APLP2 mRNA. Our findings reveal a disease-associated increase in the proportion of APP KPI-containing isoforms, and further investigation should clarify whether this predisposes affected individuals to A beta production and aggregation, or reflects later events such as gliosis and neuronal cell death.

Aged↗
PubMed1996

Impaired G-protein-stimulated adenylyl cyclase activity in Alzheimer's disease brain is not accompanied by reduced cyclic-AMP-dependent protein kinase A activity.

Previous studies have shown that the regulation of adenylyl cyclase activity is disrupted in Alzheimer's disease postmortem brain. In the present study, we determined whether disrupted adenylyl cyclase is accompanied by altered cAMP-dependent protein kinase activity in Alzheimer's disease superior temporal cortex and cerebellum. GTP gamma S-stimulated adenylyl cyclase activity was significantly lower in Alzheimer's disease superior temporal cortex, but not cerebellum, compared to values from a series of matched control cases. Neither basal or forskolin-stimulated adenylyl cyclase activities were significantly different between the Alzheimer's disease and control brain regions. No significant differences were seen in either particulate or soluble fraction cAMP-dependent protein kinase activities between the Alzheimer's disease and control brain regions. It is concluded that disrupted adenylyl cyclase signalling in Alzheimer's disease brain occurs specifically at the level of Gs-protein-enzyme interactions and is not accompanied by an altered cAMP-dependent protein kinase activity.

Adenylyl Cyclases↗
PubMed1996

Differential vasopressin and oxytocin innervation of the human parabrachial nucleus: no changes in Alzheimer's disease.

The distribution of vasopressin and oxytocin immunoreactive fibers was examined in the pontine parabrachial nucleus of the human brain using purified polyclonal antibodies. The results revealed a striking predominance of vasopressin in this brain region. No obvious density difference, either in vasopressin or in oxytocin innervation, was found between Alzheimer's disease patients and matched controls. The present study corroborates other reports that suggest that in Alzheimer's disease the vasopressin innervation in the caudal part of the human brain is not affected.

Aged↗
PubMed1996

Increase in vasopressin binding sites in the human choroid plexus in Alzheimer's disease.

Vasopressin binding sites were determined in the choroid plexus of five Alzheimer's disease patients and five non-demented controls using the 125I-labelled linear V1a-antagonist. The Alzheimer's disease patients showed a twofold increase in the density of vasopressin binding sites, whereas the increase in the affinity constant Kd did not reach significance.

Aged↗
PubMed1996

Acetylcholine muscarinic M2 receptor stimulated [35S]GTP gamma S binding shows regional selective changes in Alzheimer's disease postmortem brain.

Oxotremorine-M stimulated [35S]GTP gamma S binding was used to assess acetylcholine muscarinic M2 receptor mediated G-protein function in superior frontal cortical, superior temporal cortical and hippocampal membranes from a series of Alzheimer's disease and matched control subjects. No significant differences were seen in basal [35S]GTP gamma S binding between the groups. The maximal level of oxotremorine-M stimulated [35S]GTP gamma S binding over basal was significantly increased in Alzheimer's disease superior temporal cortex, suggesting an enhanced muscarinic M2 receptor-G-protein coupling efficiency in this region. In contrast, the maximal level of oxotremorine-M stimulated [35S]GTP gamma S binding over basal was unaltered in Alzheimer's disease superior frontal cortex and significantly reduced in Alzheimer's disease hippocampus. Western immunoblotting using antisera towards the alpha-subunits of those G-protein types known to couple muscarinic receptors, revealed that Gq alpha and Gi alpha, but not G(o) alpha, levels were significantly reduced in Alzheimer's disease superior temporal cortex. Neither Gq alpha, Gi alpha, nor G(o) alpha levels were significantly altered in Alzheimer's disease superior frontal cortex or hippocampus. These results suggest that the efficacy of muscarinic M2 receptor G-protein coupling shows regional selective changes in Alzheimer's disease postmortem brain with deficits occurring only in a region that shows severe pathology.

Age Factors↗
PubMed1995

The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis.

The identification of key antigens in human autoimmune diseases is a crucial step towards the development of specific intervention. The autoantigen(s) relevant to multiple sclerosis (MS) probably reside in myelin of the central nervous system, the target of the disease. Here we examine proliferative responses of human peripheral blood T cells to the complete collection of myelin proteins fractionated by reversed-phase high-performance liquid chromatography. Myelin isolated from MS-affected brain contained a single protein fraction to which T cells from MS patients and from healthy controls showed dominant responses. This highly immunogenic protein was identified as alpha B-crystallin, a small heat-shock protein. Immunohistochemical examination of MS lesions revealed the presence of oligodendrocytes and astrocytes with raised alpha B-crystallin expression, which were not found in unaffected myelin. Our findings indicate that alpha B-crystallin serves as immunodominant myelin antigen to human T cells when expressed at the elevated levels found in active MS lesions.

Astrocytes↗
PubMed1995

Diminished [3H]inositol(1,4,5)P3 but not [3H]inositol(1,3,4,5)P4 binding in Alzheimer's disease brain.

Levels of the calcium mobilising receptors for the phosphoinositide hydrolysis derived second messengers, inositol(1,4,5)trisphosphate [Ins(1,4,5)P3] and inositol(1,3,4,5) tetrakis-phosphate [Ins(1,3,4,5)P4] were compared in the cerebellum, superior temporal and superior frontal cortex of a series of Alzheimer's disease and matched control cases. Membrane [3H]Ins(1,4,5)P3 radioligand binding experiments performed under steady state conditions revealed that the number of Ins(1,4,5)P3 recognition sites was significantly decreased in all three brain regions of the Alzheimer's disease cases, compared to controls. In contrast, [3H]Ins(1,3,4,5)P4 binding levels, as assessed in competition analyses, were not significantly different between the groups in any brain region. Moreover, the Hill coefficients for inhibition of [3H]Ins(1,3,4,5)P4 binding by non-radioactive Ins(1,3,4,5)P4 were less than unity in both the control and Alzheimer's disease brains, suggesting that the heterogeneity of these binding sites are also maintained in the disease. It is concluded that disruptions of the phosphoinositide hydrolysis pathway in Alzheimer's disease brain are associated with a selective loss of calcium mobilising Ins(1,4,5)P3, but not Ins(1,3,4,5)P4 receptor sites. These alterations may contribute to an altered calcium homeostasis in Alzheimer's disease, as well as providing one reason for the lack of success of cholinergic replacement therapies aimed at enhancing muscarinic receptor-mediated phosphatidylinositol hydrolysis.

Aged↗
PubMed1995

Reduced nitric oxide responsive soluble guanylyl cyclase activity in the superior temporal cortex of patients with Alzheimer's disease.

Particulate and soluble guanylyl cyclase activities were studied in postmortem temporal cortex from a series of Alzheimer's disease patients and matched control subjects. Particulate guanylyl cyclase activity was not significantly different between groups. In contrast, the Vmax values for basal and sodium nitroprusside-stimulated soluble guanylyl cyclase activities were approximately 50% lower in the Alzheimer's disease cases, compared to controls. This difference between groups was statistically significant for sodium nitroprusside-stimulated, but not for the basal, enzyme activities. These results provide the first evidence for a loss of nitric oxide responsive guanylyl cyclase activity in Alzheimer's disease brain.

Aged↗
PubMed1995

Preservation of acetylcholine muscarinic M2 receptor G-protein interactions in the neocortex of patients with Alzheimer's disease.

The efficacy of acetylcholine muscarinic M2 receptor-G protein coupling was investigated in Alzheimer's disease and control neocortical membranes by measuring the effects of MgCl2 and 5'-guanylylimidodiphosphate (Gpp[NH]p) on high-affinity [3H]oxotremorine-M ([3H]OXO-M) binding. MgCl2 gave similar enhancements of [3H]OXO-M binding in Alzheimer's disease and control occipital cortex. In contrast, MgCl2 enhanced [3H]OXO-M binding was significantly higher in Alzheimer's disease superior temporal cortex, compared to controls. MgCl2 enhanced [3H]OXO-M binding in both the occipital and temporal cortices of the Alzheimer's disease cases was reversed to control levels by Gpp[NH]p. It is concluded that the number of high-affinity muscarinic M2 sites is increased in Alzheimer's disease superior temporal, but not occipital, cortex and that M2 sites in both regions maintain an efficient G-protein coupling.

Aged↗
PubMed1995

Preservation of kappa 1 opioid receptor recognition site density and regulation by G-proteins in the temporal cortex of patients with Alzheimer's disease.

The pharmacological properties of the kappa 1 opioid receptor were investigated in human post-mortem temporal cortical membranes from control and Alzheimer's disease brains, using the kappa 1-selective radioligand [3H]U69593. [3H]U69593 bound to a single high affinity site population with no significant difference between control (Bmax 31 +/- 4.14 fmol/mg protein, KD 1.01 +/- 0.26 nM) and Alzheimer's disease brains (Bmax 37 +/- 4.63 fmol/mg protein, KD 0.86 +/- 0.08 nM). Competition studies with dynorphin B and alpha-neoendorphin gave flat inhibition curves with Hill coefficients of 0.31 +/- 0.04 and 0.49 +/- 0.09 in the control brains and 0.38 +/- 0.05 and 0.48 +/- 0.08 in the Alzheimer's disease brains, respectively. The pI50 values for dynorphin B and alpha-neoendorphin were 8.73 +/- 0.17 and 8.48 +/- 0.09, respectively, in the control brains and 9.30 +/- 0.22 and 8.70 +/- 0.15 in the Alzheimer's disease brains. The guanine nucleotide analogue Gpp(NH)p inhibited binding by ca. 70% in both the control and Alzheimer's disease brains, the residual binding being sensitive to NaCl in both cases. These results indicate that the pharmacological properties and the functional integrity of G-protein coupling of the kappa 1 receptor recognition site are preserved in Alzheimer's disease temporal cortex.

Aged↗
PubMed1995

Increased activity of hypothalamic corticotropin-releasing hormone neurons in multiple sclerosis.

Clinical observations and animal studies suggest that the hypothalamo-pituitary-adrenal (HPA) axis plays a role in the susceptibility to and the recovery from multiple sclerosis (MS). Since the HPA-axis is under the control of corticotropin-releasing hormone (CRH) neurons of the hypothalamus, we determined 2 parameters for activation of the CRH neurons in the hypothalamic paraventricular nucleus (PVN) in MS patients. Since the HPA-axis is more activated in MS, we expected an increased activity of CRH neurons. We also expected to see an age-related increase in CRH activity, because of the possible role of the HPA-axis in the age-related decrease in susceptibility to MS. The number of CRH cell profiles and the proportion of CRH neurons co-expressing vasopressin were used as parameters for activity. CRH cell population became more activated both in control and MS patients, from 40 years of age onwards, when the prevalence of MS starts to decrease in the population. The CRH neurons showed a significantly higher level of activation in MS patients than in controls, as appeared from the 3-fold increase in CRH cell number and the 4.5-fold increase in cells co-expressing CRH and vasopressin (AVP).

Adult↗
PubMed1995

'Lewy body disease': clinico-pathological correlations in 18 consecutive cases of Parkinson's disease with and without dementia.

One of the characteristic histological features of Parkinson's disease (PD), with or without dementia, is the presence of Lewy bodies (LBs) in the brainstem and neocortical and limbic structures. They are often accompanied by Alzheimer type pathology (ATP). In the present retrospective study the clinical features and post-mortem findings of 18 consecutive and unselected PD patients were compared, with special reference to the frequent but not exclusive association of LBs with ATP in Lewy body disease (LBD). LBD is the term applied to a particular pattern of neuronal degeneration associated with LBs. In this study of idiopathic PD patients ATP seems to be the major determinant of the cognitive decline in most patients. Cortical Lewy Bodies (CLBs) were present in all patients reviewed, whether or not dementia was present. It was not possible to distinguish a specific pattern in the cognitive or psychopathological symptoms of dementia that would differentiate LBD from Alzheimer's disease (AD). Although in most cases hippocampal CA2-3 ubiquitin immunoreactive neurites were observed, here again there was no correlation with the presence of dementia.

Aged↗
PubMed1995

Decreased activity of hippocampal neurons in Alzheimer's disease is not related to the presence of neurofibrillary tangles.

Numerous studies have established the key role of the Golgi apparatus (GA) in post-translational processing, transport and targeting of proteins destined for secretion, lysosomes and plasma membranes. Moreover, several studies performed in our laboratories have shown that the size of the immunocytochemically detected neuronal GA is a reliable index of neuronal activity in aging, Alzheimer's disease (AD) and amyotrophic lateral sclerosis. It has been suggested that in AD there is decreased neuronal activity, e.g. in terms of glucose metabolism and protein synthetic capability. To further explore the hypothesis of decreased neuronal activity in AD, in this study the size of the GA was measured in pyramidal neurons of the CA1 area of the hippocampus of non-demented controls and AD patients. The size of the GA was measured separately in neurons with and without neurofibrillary tangles (NFT). Moreover, in order to establish a correlation between the density of NFT and the size of the GA, the density of extraneuronal NFT was determined around each neuron and related to the size of its GA. The results, quantified by image analysis, indicate that there is a significant reduction in GA size in the neurons of the CA1 area of the hippocampus of AD patients. However, there was no significant relationship between the size of the GA and the presence or absence of intracellular NFT. In addition, there was no correlation between the density of extracellular NFT and GA size of adjacent neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Increased number of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of patients with multiple sclerosis.

Observations in experimental allergic encephalomyelitis (EAE), a model for multiple sclerosis (MS), have indicated that a low activity of the hypothalamo-pituitary-adrenal (HPA) system is accompanied by a high susceptibility for EAE in rat strains and that elevated corticosteroid levels are necessary for spontaneous recovery from EAE. The HPA axis activity is regulated by both corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). Both types of neurons are localized in the paraventricular nucleus (PVN) of the hypothalamus. We determined the number of immunocytochemically identified CRH-immunoreactive (CRH-IR) and AVP-immunoreactive (AVP-IR) neurons in the PVN of the human hypothalamus of 8 MS patients, aged 34-63 years, and 8 age-matched control subjects without any primary neurological or psychiatric disorders, aged 30-59 years. In addition, the number of oxytocin (OXT) immunoreactive (OXT-IR) neurons was determined, since these neurons innervate brain stem nuclei and might thus be related to autonomic disturbances in MS. In MS the staining intensity for AVP was clearly lower and for OXT slightly lower. For CRH, the staining intensity was similar in both groups, and, moreover, in MS patients the number of CRH-IR cells in the PVN was found to be about 2.4 times higher than that in the control group. The number of OXT-IR or AVP-IR cells in the PVN of MS patients was not significantly different from that of the control group. Our results point to an activation of the neuroendocrine HPA axis which may be compatible with the idea that the HPA axis is involved in recovery from MS.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗