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Biomedical subjects

H M Wisniewski

Publications and source records attributed to H M Wisniewski.

At least 37 records · Page 2Linked to original sources
PubMed1999

Relationship of calcium-binding protein containing neurons and projection neurons in the rat basolateral amygdala.

Two-laser and two-color approaches were used to observe the colocalization of the calcium-binding proteins, calbindin D28k and parvalbumin, and the retrograde tracer, Fluoro-Gold (FG) in the basolateral amygdala of the rat. The study was performed on five adult rats into which FG was injected to the frontal association cortex. Then, the localization of the retrogradely labeled neurons in the basolateral amygdala was compared with the localization of the neurons labeled by calcium-binding proteins. The present study showed that most of the retrogradely labeled neurons in the posterior part of the basolateral amygdala are also calbindin-positive. Even though a lot of parvalbumin-positive endings were present at the surface of the retrogradely labeled cells, we did not observe the colocalization of the parvalbumin and projective neurons.

Amygdala↗
PubMed1999

The therapeutic effect of an herbal formula Badmaev 28 (padma 28) on experimental allergic encephalomyelitis (EAE) in SJL/J mice.

A herbal formula, Badmaev 28, was evaluated in the treatment of an induced attack in a chronic relapsing model of experimental allergic encephalomyelitis (EAE) in SJL/J mice. Chronic EAE was induced by immunization of 8 week old mice with an emulsion of syngeneic spinal cords with incomplete Freund's adjuvant supplemented with Mycobacterium tuberculosis. Therapy with Badmaev 28 was started on day 25 after the immunization, and the formula was administered in the drinking water at doses of 7, 21, 83 and 166 mg/kg/day. The treatment resulted in significantly decreased mortality compared with the untreated control animals and the therapeutic effect occurred in one experiment in a dose-dependent fashion. Based on the experimental results it is difficult to name one particular mechanism responsible for the therapeutic effectiveness of the formula in the EAE model. Rather this protective effect could be explained by a broad protective mechanism of action discussed in the literature as nonspecific resistance (NSR) to the diversified biological and psychological stressors. The increase in NSR characterizes the action of pharmacological compounds termed adaptogens or bioprotectants.

Animals↗
PubMed1999

Plasma amyloid beta-peptide 1-42 and incipient Alzheimer's disease.

Mutations in the amyloid precursor protein and presenilin 1 and 2 genes result in elevated plasma levels of the amyloid beta-peptide species terminating at amino acid residue 42 (A beta1-42). In a longitudinal study of unrelated elderly individuals, those who subsequently developed Alzheimer's disease had higher plasma levels of A beta1-42 at entry than did those who remained free of dementia. The results indicate that elevated plasma levels of the released A beta peptide A beta1-42 may be detected several years before the onset of symptoms, supporting that extracellular A beta1-42 plays an important role in the pathogenesis of late-onset Alzheimer's disease.

Age of Onset↗
PubMed1999

Entorhinal cortex of aged subjects with Down's syndrome shows severe neuronal loss caused by neurofibrillary pathology.

In Alzheimer's disease (AD), neurofibrillary degeneration of neurons starts in the transentorhinal cortex and spreads in a time-dependent manner to the entorhinal cortex, which provides a major input to the hippocampus--a key structure of the memory system. People with Down's syndrome (DS) develop neurofibrillary changes more than 30 years earlier than those with sporadic AD. To characterize AD-related pathology in the entorhinal cortex in DS, we examined seven subjects with DS of 60-74 years of age who died in the end stage of AD, and four age-matched control subjects. The volume of the entorhinal cortex in brains of subjects with DS was 42% less than that in control cases; however, the total number of neurons free of neurofibrillary changes was reduced in DS by 90%: from 9,619,000 +/- 914,000 (mean +/- standard deviation) to 932,000 +/- 504,000. The presence of 2,488,000 +/- 544,000 neurofibrillary tangles in the entorhinal cortex of people with DS, the prevalence of end-stage tangles, and the significant negative correlation between the total number of intact neurons and the percentage of neurons with neurofibrillary changes indicate that neurofibrillary degeneration is a major cause of neuronal loss in the entorhinal cortex of people with DS. The relatively low amyloid load (7 +/- 1%) and lack of correlation between the amyloid load and the volumetric or neuronal loss suggest that the contribution of beta-amyloid to neuronal loss in the entorhinal cortex is unsubstantial.

Aged↗
PubMed1999

Alteration of free radical metabolism in the brain of mice infected with scrapie agent.

Alteration of free radical metabolism in the mouse brain by scrapie infection was evaluated. The infection of mice with scrapie agent, 87V strain, slightly increased the activities of catalase and glutathione-S-transferase, while it had no effect on glutathione peroxidase, glutathione reductase, and Cu, Zn-superoxide dismutase. Results show that the scrapie infection decreased the activity of mitochondrial Mn-superoxide dismutase by 50% but increased that of monoamine oxidase (p < 0.05). Scrapie infection also increased the rate of mitochondrial superoxide generation (p < 0.05). Following scrapie infection, the level of free-sulfhydryl compounds in brain homogenates slightly decreased, but the content of thiobarbituric-acid-reactive substances and malondialdehyde increased significantly. Electron microscopy indicated that the ultrastructure of mitochondria was destroyed in the brain of scrapie-infected mice. These results suggest that elevated oxygen free radical generation and lowered scavenging activity in mitochondria might cause the free radical damage to the brain. Such deleterious changes in mitochondria may contribute to the development of prion disease.

Animals↗
PubMed1999

Apolipoprotein E alters metabolism of AbetaPP in cells engaged in beta-amyloidosis.

Canine smooth muscle cells (SMCs), cultured from amyloid-affected brain blood vessels accumulate Alzheimer amyloid-beta peptide (Abeta) intracellularly, either spontaneously or after treatment with apolipoprotein E (apoE). ApoE is codeposited with Abeta, which suggests that apoE participates in Abeta accumulation. We tested the hypothesis that apoE-induced accumulation of Abeta in SMCs is caused by an increased production of amyloid-beta precursor protein (AbetaPP) and/or its altered metabolism. We found that 24 hours of treatment with apoE3 or apoE4 induced intracellular accumulation of Abeta-immunoreactive deposits in SMCs but did not influence AbetaPP production and processing. The treatment with apoE3 or E4 for 3 days resulted in the following: increased Abeta-accumulation; reduced levels of secreted Abeta; increased production and cellular retention of mature AbetaPP770; and reduced culture growth, cell proliferation, and viability. ApoE4, but not apoE3, increased cellular levels of mRNA AbetaPP 770 (the main form produced in SMCs) about ninefold. ApoE3 stimulated production and cellular retention of endogenous apoE. We hypothesize that Abeta accumulation is triggered by apoE, which may bind and immobilize soluble Abeta produced in SMCs. The newly formed Abeta deposits may further accelerate Abeta accumulation by altering metabolism of AbetaPP.

Amyloid beta-Protein Precursor↗
PubMed1999

Cellular processing of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type.

An important gap in our understanding of the pathogenesis of the amyloidoses is the identification of the cellular events that lead from synthesis of an amyloid precursor protein to its conversion to the amyloid fiber subunit. We address this question by characterizing the effects of an amyloidogenic mutation on the intracellular processing of its protein product. The protein, a mutant of the cysteine protease inhibitor cystatin C, is the amyloid precursor protein in Hereditary Cerebral Hemorrhage with Amyloidosis--Icelandic type (HCHWA-I). The amyloid fibers are composed of mutant cystatin C (L68Q) that lacks the first 10 amino acids. We have previously shown that processing of wild-type cystatin C entails formation of a transient intracellular dimer that dissociates prior to secretion, such that extracellular cystatin C is monomeric. We report here that the cystatin C mutation engenders several alterations in its intracellular trafficking. It forms a stable intracellular dimer that is partially retained in the endoplasmic reticulum and degraded. The bulk of mutant cystatin C that is secreted does not dissociate and is secreted as an inactive dimer. Thus, formation of the stable mutant cystatin C dimer is an early event in the pathogenesis of this disease.

Amino Acid Sequence↗
PubMed1999

Expression and distribution of various antigens of developing microglial cells in the rat telencephalon.

The distribution of microglia during the early stages of postnatal development in the rat was studied on rat brain from day of birth to postnatal day 90 (P90), using immunohistochemical methods with a panel of monoclonal antibodies that recognized the complement type 3 receptor (OX-42), macrophage antigen of unknown function (ED1), and the major histocompatibility complex (MHC) class I (OX-18) or class II (OX-6) antigens. Starting from the day of birth, ameboid microglia can be differentiated with positive immunoreactivity to OX-42, OX-18, and ED1. Labeled cells were localized mainly in the developing white matter. After P21, only positive reaction to OX-42 was present, and those cells had the typical morphology of the resting microglial cells that were located either in the white or grey matter. The changes in the appearance of different antigens are correlated with the morphological differentiation and transformation of ameboid microglial cells that are to become ramified microglia, present in the adult animals.

Aging↗
PubMed1998

Mitotic index and Alzheimer's disease.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is diagnosed definitively by increased numbers of beta-amyloid plaques and neurofibrillary tangles in brain biopsy or autopsy specimens. There are no simple straightforward laboratory tests currently available for clinical diagnosis. We have found consistent reduction in mitotic index levels in skin fibroblast cultures from AD individuals compared with age- and sex-matched controls. These differences were enhanced by overnight exposure to colcemid (p = 0.04). Results suggest that mitotic index in skin fibroblasts cultures should be further investigated as a potential diagnostic indicator for AD.

Aged↗
PubMed1998

Neuronal and volume loss in CA1 of the hippocampal formation uniquely predicts duration and severity of Alzheimer disease.

In a series of multiple regression models predicting either duration or severity of Alzheimer disease (AD) patients, significant linear correlations were found consistently for the volume of CA1, the subiculum, and the entorhinal cortex. Similarly, the total number of neurons in CA1, CA4, and the subiculum was correlated significantly with both the duration and the severity of AD. A hierarchical multiple regression model was used to examine whether any of these intercorrelated measures had any unique relationship to disease duration or severity. The results showed that only CA1 demonstrated a unique contribution to the explained variance in predicting duration or severity of AD for volume and for neuronal numbers. These results indicate that in the hippocampal formation, volume and neuronal numbers of CA1 appear to show a unique relationship with clinical measures of AD.

Alzheimer Disease↗
PubMed1998

Region- and cell-type-specific pattern of tau phosphorylation in dog brain.

A study of brains of 16 dogs from one to 19 years of age showed a structure- and cell-type- specific pattern of tau protein phosphorylation at mAb Tau-1 site and the absence of phosphorylation at the mAb AT8 site. Strong immunolabeling with mAb Tau-1 of the mossy fibers and perikarya of neurons in sectors CA3 and CA4 of the cornu Ammonis, less intensive staining in the cytoplasm in neocortical and subcortical neurons, and selective staining of some pyramidal cells in sectors CA1 and CA2 show differences in the amount of phosphorylated tau, not only in different types of neurons, but also in different parts of the cell. The immunoreactivity of oligodendrocytes and the absence of the reaction in astrocytes reflect differences in tau phosphorylation in glial cells. Marked immunoreactivity in 13 dogs but minimal reaction in brains of three other dogs appears to reflect interindividual differences, which are associated presumably with genetic background. Shrinkage of neurons, tortuosity of mossy fibers, accumulation of phosphorylated tau in the nucleoplasm, and deformation of the nuclei of neurons and oligodendrocytes suggest that excessive phosphorylation at the mAb Tau-1 site is associated with neuronal and oligodendrocyte degeneration and, possibly, cell death.

Amyloid beta-Peptides↗
PubMed1998

Duration of neurofibrillary changes in the hippocampal pyramidal neurons.

The total number of neurons with and without neurofibrillary changes in sectors CA1 to CA4, subiculum, and dentate gyrus of 16 subjects with Alzheimer disease (AD) was estimated. The duration of neurofibrillary changes was calculated on the basis of regressions between the duration of AD and neuronal numbers. In the CA1 and subiculum, it takes 3.4 and 5.4 years, respectively, for an intact neuron affected by neurofibrillary pathology to become a ghost tangle.

Aged↗
PubMed1998

Longitudinal study of cerebrospinal fluid amyloid proteins and apolipoprotein E in patients with probable Alzheimer's disease.

Levels of soluble amyloid beta protein (sAbeta), amyloid beta precursor protein (APP) and apolipoprotein E (apoE) were examined in cerebrospinal fluid (CSF) obtained twice, at baseline and after 3-year follow-up, from 25 patients with probable Alzheimer's disease (AD). Levels of sAbeta and apoE from patients with the apoE4 allele decreased with time, whereas the levels were similar in patients without apoE4 allele. Changes of sAbeta and apoE concentrations correlated significantly with those of mini-mental state examination (MMSE) scores. Levels of sAbeta did not change with time in patients with mild dementia, whereas they decreased significantly in patients with moderate dementia. ApoE concentrations decreased in both groups whereas APP levels were similar. We conclude that measurements of CSF sAbeta and apoE levels may be helpful in monitoring progression of the disease.

Aged↗
PubMed1998

Aggregation of amyloid beta-protein as function of age and apolipoprotein E in normal and Alzheimer's serum.

We compared the effect of serum from (a) 26 Alzheimer's disease (AD) patients and 22 age-matched non-demented controls (CO) with apolipoprotein E 4/4, 3/3 or 3/2 phenotypes, and (b) 17 normal young (aged 15-41 years) and 21 normal elderly (aged 64-83 years) people on in vitro aggregation of synthetic amyloid beta-protein (A beta) 1-40 by Thioflavin T fluorescence spectroscopy. A beta 1-40 aggregation in presence of serum from the normal elderly group was significantly higher as compared to the normal young group (correlation coefficient between age and A beta aggregation=0.73). However, no difference in A beta aggregation was observed in the presence of serum from AD patients and non-demented controls. There was a positive correlation between serum apo E concentrations and A beta aggregation, while there was no significant difference between different apo E phenotypes. The correlation coefficient in the AD 4/4 (0.65) was higher than the CO 4/4 group (0.04), while it was lower in the AD 3/3 group (-0.12) than in the CO 3/3 (0.39) group. These results suggest that the apo E4 allele alone may not be responsible for A beta fibril formation in AD; other factors may be involved in increasing risk for AD pathogenesis in those having the apo E4 allele. The severity of dementia and serum albumin levels also did not correlate with A beta aggregation. We propose that the age of an individual may be an important factor in determining the degree of A beta aggregation/fibrillization, and that mechanism of sequestration of A beta in serum may not be defective in AD.

Adolescent↗
PubMed1998

A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years.

The majority of early-onset familial Alzheimer's disease (FAD) is associated with mutations in the presenilin-1 (PS1) gene. We describe a novel Polish PS1 mutation of Pro117Leu, associated with the earliest average age of onset and death so far reported in a PS-linked, FAD kindred. Human kidney 293 and mouse neuroblastoma N2a cells were stably transfected with wild-type and PS1 P117L. There was a significant increase in the amyloid beta42/40 ratio in the N2a P117L PS1 transfected cells compared with N2a transfected with wild-type PS1. What role PS has in the pathogenesis of AD remains to be determined, however, the severity of the clinical picture associated with this PS1 mutation stresses the importance of presenilin.

Adult↗
PubMed1998

Increased plasma amyloid beta protein 1-42 levels in Down syndrome.

Amyloid beta protein 1-40 (A beta40) and A beta42 levels were quantitated in plasma from 43 persons with Down syndrome (DS; 26-68 years of age), 43 age-matched normal controls, and 19 non-DS mentally retarded (MR) persons (26-91 years of age) by using a sandwich enzyme linked immunosorbent assay. A beta40 levels were higher in DS and MR than controls, but were similar between DS and MR groups. A beta42 levels were higher in DS than controls or MR persons. The ratios of A beta42/A beta40 were higher in DS than controls or MR persons. The findings are consistent with those seen in DS brains.

Adult↗
PubMed1998

N-methyl-D-aspartate receptor-mediated, calcium-induced calcium release in rat dentate gyrus/CA4 in vivo.

Previously, by using in vivo microdialysis, we demonstrated a huge release of 45Ca2+ from prelabeled tissues to dialysate that was evoked by application of N-methyl-D-aspartate (NMDA) to the rat dentate gyrus (DG) and sector 4 of the cornu ammonis. To establish the mechanism of this phenomenon, in the present study, we characterized its NMDA receptor dependence, investigated the mechanism of 45Ca2+ removal from the cells, and evaluated the possible involvement of calcium-binding protein calbindin D28k and of ryanodine receptors. Microdialysis experiments demonstrated a dose-response relation between NMDA and 45Ca2+ release and sensitivity of this phenomenon to inhibition by 10 microM MK-801 and 5 mM 5-(N,N-dimethyl)-amiloride, thus indicating the NMDA receptor dependence and a role of Na+/Ca2+ exchanger in mediating 45Ca2+ release from cells. Immunocytochemical experiments confirmed that DG granule cells in the investigated inbred rat strain are strongly calbindin D28k-immunopositive, indicating probable involvement of this protein. However, microdialysis studies demonstrated that NMDA-evoked 45Ca2+ release was suppressed by 100 microM dantrolene and 250 microM ryanodine, whereas 50 microM ryanodine stimulated this effect. This points to a key role in the investigated phenomenon of calcium-induced calcium release (CICR) via ryanodine receptors. To our knowledge, this is the first in vivo demonstration of NMDA-evoked CICR. We postulate the usefulness of microdialysis in such studies.

Animals↗