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Biomedical subjects

Y Kress

Publications and source records attributed to Y Kress.

At least 19 recordsLinked to original sources
PubMed2001

Mitochondrial abnormalities in Alzheimer's disease.

The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we used in situ hybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.

Adolescent↗
PubMed2001

Intracellular crystal formation as a mechanism of cytotoxicity in murine pulmonary Cryptococcus neoformans infection.

Rod-like crystalline structures formed during eosinophilic Cryptococcus neoformans pneumonia in C57BL/6 mice. Crystals were found associated with yeast cells and free in host cell cytoplasm. The crystals apparently formed because of the interaction of a host protein with the cryptococcal polysaccharide. Crystal formation likely contributes to pathogenesis by causing cellular damage.

Animals↗
PubMed2000

The effect of the echinocandin analogue caspofungin on cell wall glucan synthesis by Cryptococcus neoformans.

The echinocandin derivative caspofungin (MK-0991, L-743,872) inhibits 1,3-beta-d-glucan synthesis and is active against several medically important fungi but is relatively ineffective against Cryptococcus neoformans. To investigate the mechanism of C. neoformans resistance, the prevalence of 1,3- and 1,6-beta-d-glucan linkages was determined in cells grown with and without caspofungin, using affinity-purified antisera and gold particle immunoelectron microscopy. Cryptococcal strains ATCC 24067 (serotype D) and MY2061 (serotype A) were studied. Growth at 4 microg/mL of caspofungin reduced both glucan linkages in both strains. However, growth at 2 microg/mL resulted in reduced 1,6-beta-d-glucan linkage only for MY2061. Inhibition of 1,6-beta-d-glucan synthesis may be an additional mechanism of action for pneumocandins. The relatively low efficacy of caspofungin against C. neoformans may result from reduced activity against C. neoformans glucan synthase or from yet undiscovered mechanisms of action operative in other fungal pathogens but not in C. neoformans.

Animals↗
PubMed2000

Novel microtubule-associated protein-2 isoform is expressed early in human oligodendrocyte maturation.

We have identified a developmentally regulated, oligodendrocyte-specific protein, designated microtubule-associated protein-2 expressing exon 13 (MAP-2+13), in the human central nervous system (CNS). Monoclonal antibodies directed against MAP-2+13 labeled oligodendrocytes in the white matter of human fetal spinal cord. Double-label immunofluorescence and confocal microscopy, and immunoelectron microscopy localized MAP-2+13 to the soma and extending processes of fetal oligodendrocytes, but not to the myelin sheath. The immunoreactivity was throughout the perikarya. Ultrastructural examination of the fetal myelin sheaths showed them to be thin and not fully compacted, indicating that myelination was in progress. There was no overlap in staining of GFAP+ astrocytes and MAP-2+13+ oligodendrocytes. MAP-2+13 was also expressed in intermediate filament-negative "radial glia" extending from the central canal to the subpial surface. In the mature CNS, MAP-2+13 also marked cells of oligodendroglial morphology, but these cells were rare. These finding demonstrate that in the human CNS, MAP-2+13 is a novel protein transiently expressed in cells of oligodendroglial lineage.

Antibodies, Monoclonal↗
PubMed2000

Induction of Alzheimer-specific Tau epitope AT100 in apoptotic human fetal astrocytes.

In Alzheimer's and other neurodegenerative diseases, hyperphosphorylated tau accumulates in affected neuronal and glial cells in the form of paired helical filaments (PHFs). This tau binds antibody AT100, which recognizes the double phosphorylation site (Thr212/Ser214) that is not present in normal biopsy tau. In primary cultures, highly enriched (>98%) in astrocytes of human fetal brain, three polypeptides of 52, 64, and 70 kD showed immunoreactivity with tau antibodies against non-phosphorylated epitopes, accounting for 88, 12, and <1%, respectively, of the total reactivity. All three polypeptides were phosphorylated at the PHF-1 epitope but not at the epitopes Tau-1, 12E8, AT8, and AT100. Treatment of cultures with okadaic acid resulted in apoptosis characterized by the blebbing of the plasma membrane, condensation of nuclear chromatin, and fragmentation of the nucleus. This treatment also resulted in a 3- to 5-fold increase in the content of both tau protein and phosphorylation. The increases were observed in all phosphorylation sites examined, and included the AT100 site. The AT100 site has been proposed to be generated by protein kinase B/Akt and Cdc2. Since okadaic acid can induce an AD-like hyperphosphorylated state of normal tau in primary cultures of human brain cells, a simple cellular model is available permitting study of self-aggregation of tau and phosphorylation events characteristic of neurodegeneration.

Alternative Splicing↗
PubMed2000

Intracellular passage within macrophages affects the trafficking of virulent tubercle bacilli upon reinfection of other macrophages in a serum-dependent manner.

SETTING: The interaction of tubercle bacilli with macrophages is central to understanding of tuberculosis disease. OBJECTIVE: The objective was to determine whether prior passage within macrophages affects the behavior of Mycobacterium tuberculosis (Mtb) upon re-entry into other macrophages. DESIGN: Transmission electron microscopy was used to monitor fusion of bacterial phagosomes with late endosomal/lysosomal compartments using thoria as a fluid phase marker. Two-dimensional polyacrylamide gel electrophoresis was used to study bacterial protein expression within macrophages. RESULTS: H37Rv and BCG expressed novel proteins within macrophages. H37Rv also underwent less fusion after intracellular (IC) (24.2+/-7.7%) than extracellular (XC) (67.4+/-5.5%) passage when the bacteria entered new macrophages in small clusters. These effects were inhibited by serum, and were not observed with H37Ra or BCG bacteria (78.9+/-1.6% fused for all conditions). In addition, vacuoles which contained single bacilli were less likely to acquire markers (26.9+/-2.6%) than those that contained multiple bacilli (77.3+/-2.8%). CONCLUSION: These results indicate that phagolysosomal fusion patterns can be modulated by a variety of factors and that virulent Mtb bacteria may express proteins within macrophages that alter their interaction with these host cells.

Animals↗
PubMed2000

Antibody interactions with the capsule of Cryptococcus neoformans.

Monoclonal antibodies to the encapsulated fungus Cryptococcus neoformans produce different immunofluorescence (IF) patterns after binding to the polysaccharide capsule. To explore the relationship between the IF pattern and the location of antibody binding, two immunoglobulin M (IgM) monoclonal antibodies (MAbs) (12A1 and 13F1) that differ in protective efficacy and IF pattern and one protective IgG1 MAb (2H1) were studied by IF and electron microscopy (EM). Fixing C. neoformans cells in lung tissue for EM resulted in significantly better preservation of the capsule than fixing yeast cells in suspension. The localization of MAbs 12A1 and 13F1 by immunogold EM differed depending on whether the MAb was bound to cells in cut tissue sections embedded in plastic or to cells in solution. In cut tissue sections, MAbs 12A1 and 13F1 bound throughout the capsule, whereas in solution both MAbs bound near the capsule surface. To investigate whether antibody binding to the C. neoformans capsule affected the binding of other primary or secondary reagents, various combinations of MAbs 12A1, 13F1, and 2H1 were studied by direct and indirect IF. The IF pattern and location of binding for MAbs 12A1, 13F1, and 2H1 varied depending on the presence of other capsule-binding MAbs and the method of detection. The results show that (i) binding of MAbs to the C. neoformans polysaccharide capsule can modify the binding of subsequent primary or secondary antibodies; (ii) the IgM MAbs bind primarily to the outer capsule regions despite the occurrence of their epitopes throughout the capsule; and (iii) MAb 2H1 staining of newly formed buds is reduced, suggesting quantitative or qualitative differences in bud capsule.

Animals↗
PubMed2000

Cryptococcus neoformans is a facultative intracellular pathogen in murine pulmonary infection.

To produce chronic infection, microbial pathogens must escape host immune defenses. Infection with the human pathogenic fungus Cryptococcus neoformans is typically chronic. To understand the mechanism by which C. neoformans survives in tissue after the infection of immunocompetent hosts, we systematically studied the course of pulmonary infection in mice by electron microscopy. The macrophage was the primary phagocytic cell at all times of infection, but neutrophils also ingested yeast. Alveolar macrophages rapidly internalized yeast cells after intratracheal infection, and intracellular yeast cells were noted at all times of infection from 2 h through 28 days. However, the proportion of yeast cells in the intracellular and extracellular spaces varied with the time of infection. Early in infection, yeast cells were found predominantly in the intracellular compartment. A shift toward extracellular predominance occurred by 24 h that was accompanied by macrophage cytotoxicity and disruption. Later in infection, intracellular persistence in vivo was associated with replication, residence in a membrane-bound phagosome, polysaccharide accumulation inside cells, and cytotoxicity to macrophages, despite phagolysosomal fusion. Many phagocytic vacuoles with intracellular yeast had discontinuous membranes. Macrophage infection resulted in cells with a distinctive appearance characterized by large numbers of vacuoles filled with polysaccharide antigen. Similar results were observed in vitro using a macrophage-like cell line. Our results show that C. neoformans is a facultative intracellular pathogen in vivo. Furthermore, our observations suggest that C. neoformans occupies a unique niche among the intracellular pathogens whereby survival in phagocytic cells is accompanied by intracellular polysaccharide production.

Animals↗
PubMed1999

cAMP-dependent protein kinase phosphorylations on tau in Alzheimer's disease.

To elucidate the role cAMP-dependent protein kinase (PKA) phosphorylations on tau play in Alzheimer's disease, we have generated highly specific monoclonal antibodies, CP-3 and PG-5, which recognize the PKA-dependent phosphorylations of ser214 and ser409 in tau respectively. The present study demonstrates by immunohistochemical analysis, CP-3 and PG-5 immunoreactivity with neurofibrillary pathology in both early and advanced Alzheimer's disease, but not in normal brain tissue and demonstrates that cAMP-dependent protein kinase phosphorylations on tau precede or are coincident with the initial appearance of filamentous aggregates of tau. Studies using heat-stable preparations demonstrate that neither site appears to be phosphorylated to any appreciable extent in normal rodent or human brain. Further analysis demonstrates that the beta catalytic subunit of PKA (Cbeta), the beta II regulatory subunit of PKA (RIIbeta), and the 79 kDa A-kinase-anchoring-protein (AKAP79), are tightly associated with the neurofibrillary pathology, positioning cAMP-dependent protein kinase to participate directly in the pathological hyperphosphorylation of tau seen in Alzheimer's disease.

Alzheimer Disease↗
PubMed1999

The M cell as a portal of entry to the lung for the bacterial pathogen Mycobacterium tuberculosis.

M. tuberculosis accesses the terminal lung and is phagocytosed by alveolar macrophages. Utilizing a mouse intratracheal challenge model, we demonstrate that M. tuberculosis rapidly enters through M cells as well. From there, bacilli are deposited within associated intraepithelial leukocytes and subsequently conveyed to the draining lymph nodes early after infection. Osteopetrotic (Csfm(op)/Csfm(op)) mice, null mutants for macrophage colony-stimulating factor, possess diminished numbers of circulating monocytes and tissue macrophages. Csfm(op)/Csfm(op) mice were highly susceptible to challenge with M. tuberculosis. In contrast to controls, tubercle bacilli were not conveyed to draining lymph nodes early after infection but were instead retained within the mucosa. These results indicate that M cells represent an alternate portal of entry for M. tuberculosis, which may contribute to the rapid development of protective lung immune responses.

Animals↗
PubMed1999

A novel microtubule-associated protein-2 expressed in oligodendrocytes in multiple sclerosis lesions.

Elucidation of the mechanisms involved in the regeneration of oligodendrocytes and remyelination is a central issue in multiple sclerosis (MS) research. We recently identified a novel alternatively spliced, developmentally regulated oligodendrocyte-specific protein designated microtubule-associated protein-2+13 [microtubule-associated protein-2 expressing exon 13 (MAP-2+13)]. MAP-2+13 is expressed in human fetal oligodendrocytes during process extension and myelination but is minimally expressed in normal mature CNS. To test the hypothesis that MAP-2+13 is reexpressed in regenerating oligodendrocytes in MS lesions, we examined the brains of MS patients for the expression of this protein. By immunocytochemistry using a series of monoclonal antibodies specific for MAP-2+13, we determined that MAP-2+13 expression was up-regulated in all 31 lesions from 10 different MS brains. MAP-2+13 was expressed in regenerating oligodendrocytes associated with demyelinated lesions, with the highest counts found in regions of extensive remyelination. By electron microscopy, MAP-2+13 was localized to oligodendrocytes engaged in remyelination, evident by their process extension and association with thinly myelinated (remyelinated) and demyelinated axons. These results suggest a hitherto unsuspected role for this microtubule-associated protein in oligodendrocyte function during development and myelin repair.

Adult↗
PubMed1999

Herpesvirus-associated papillomas in koi carp (Cyprinus carpio).

From January through November 1994, 32% (7/22) of koi carp (Cyprinus carpio) maintained in indoor aquariums developed proliferative cutaneous lesions that consisted of single to multiple 2-10-mm whitish to pink fleshy masses usually associated with fin rays. Although scaleless koi were more commonly affected (3/6) than were normally scaled koi (4/16), the difference in incidence rates was not significant (chi2 text, P > 0.05). Lesions typically resolved spontaneously in 1-3 wk, occasionally persisted for >3 mo, and recurred in several fish after 2-5 mo. Fish were otherwise asymptomatic. Wet mount preparations from lesions were densely cellular and consisted of hyperplastic epidermal cells of normal morphology without parasites or inflammatory cells. Histologically, biopsies were consistent with papillomas and were characterized by a marked benign epidermal hyperplasia without inclusion bodies or inflammatory infiltrate. Transmission electron microscopic examination revealed intranuclear and intracytoplasmic herpesvirus virions. Virus isolation attempts were unsuccessful.

Animals↗
PubMed1998

Molecular and functional characteristics of MAP-2a: ability of MAP-2a versus MAP-2b to induce stable microtubules in COS cells.

Microtubule-associated protein-2 (MAP-2) is a prominent cytoskeletal protein in the mammalian nervous system. Two high-molecular-weight (HMW) MAP-2 isoforms, MAP-2a and MAP-2b, are developmentally regulated. MAP-2b is expressed through the life of the neuron, while MAP-2a expression coincides with the time of synaptic formation. MAP-2a and MAP-2b differ in size by approximately 10 kD. Attempts to differentiate MAP-2a from MAP-2b led to the identification of additional exons; exons 7A, 8, 13, and 16. The focus of the present study was to define the complete molecular composition of MAP-2a that was prerequisite for investigating the functional characteristic of the MAP-2a protein. Detailed examination of rat brain mRNA by Northern blot analysis and RT-PCR showed that MAP-2a contains only exon 8 in addition to the exons found in the MAP-2b transcript. Exons 7A, 13, and 16 are not present in the MAP-2a transcript. Antibody generated to exon 8 expressed protein, immunoprecipitated a HMW protein from adult rat brain that co-migrated with MAP-2a and was immunopositive with other MAP-2 antibodies. Comparative transfections of full-length MAP-2a and MAP-2b cDNA into COS-7 cells demonstrated that MAP-2a influenced the microtubule network differently than MAP-2b by inducing rapid and stable microtubule bundle formation even in the presence of nocodazole.

Animals↗
PubMed1998

Non-plaque dystrophic dendrites in Alzheimer hippocampus: a new pathological structure revealed by glutamate receptor immunocytochemistry.

Alzheimer's disease is a progressive dementia characterized by a pronounced neurodegeneration in the entorhinal cortex, hippocampal CA1, and subiculum. Excitatory amino acid receptor-mediated excitotoxicity is postulated to play a role in the neurodegeneration in Alzheimer's disease. The present study investigated immunocytochemical localization of excitatory amino acid receptor subunits in the hippocampus of twelve Alzheimer's disease and eleven controls, matched for age, sex and post mortem interval. Immunocytochemistry with antibodies specific for glutamate receptors GluR1, GluR2(4) (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid), GluR5/6/7 (kainate) and NR1 (N-methyl-D-aspartate) receptor subunits demonstrated that virtually all projection neurons in all subfields contained subunits from each receptor class. However, regional differences in immunoreactivity were apparent in Alzheimer's disease vs normal human brain. In the vulnerable regions (i.e. CA1) immunolabelling of GluR1, GluR2(4), GluR5/6/7 and NR1 was reduced, presumably due to cell loss. In contrast, GluR2(4) immunolabelling appeared to be increased in the inner portion of the molecular layer of the dentate gyrus. In addition to cellular labelling, GluR1, GluR2(4) and NR1 immunolabelling revealed a novel pathological structure in 12 of 12 Alzheimer's disease, but none of the control brains. The lesions were juxtacellular clusters of granular immunoreactivity in the neuropil of the pyramidal cell layer. Ultrastructural analysis revealed these to be cellular processes containing dense vesicles and flocculent material with immunolabelling localized to plasma and vesicular membranes. They were not specifically associated with amyloid fibrils and did not contain paired helical filaments and they were also distinct from granulovacuolar degeneration. Several structures contained Hirano body filaments indicating that the dystrophic processes were most likely dendritic in origin. Additional studies are needed to determine the pathogenesis of these lesions, which could provide an additional index of dendritic deterioration in Alzheimer's disease.

Aged↗
PubMed1998

Effect of antibody to capsular polysaccharide on eosinophilic pneumonia in murine infection with Cryptococcus neoformans.

The effect of the murine IgG1 monoclonal antibody (MAb) 2H1, which binds to Cryptococcus neoformans glucuronoxylomannan (GXM), on pulmonary infection in immunocompetent C57Bl/6 mice was examined. C57Bl/6 mice develop eosinophilic pneumonia in response to pulmonary cryptococcal infection. Survival, organ fungus burden, serum anticapsular antibody levels, and histopathology by light and electron microscopy were studied. MAb administration prior to infection prolonged survival without reducing the number of yeast in the lung or extrapulmonary sites. Compared with uninfected mice, occasional control and MAb-treated mice produced more IgM antibody to GXM or low levels of GXM-binding IgG1, IgG2b, or IgG3 antibodies. MAb-treated mice had fewer granules per eosinophil, indicating alteration in eosinophil physiology or degranulation (or both). Our results provide additional evidence that antibody administration can produce quantitative and qualitative changes in the inflammatory response to a pathogen.

Animals↗
PubMed1997

Expression of microtubule-associated protein-2a and other novel microtubule-associated protein-2 transcripts in human fetal spinal cord.

In human fetal spinal cord (HFSC), six additional microtubule-associated protein-2 (MAP-2) transcripts are generated by alternative splicing of two recently described exons, exon 8 and exon 13. The following three translated proteins are detected by western blot analysis: MAP-2b expressing exon 8 (MAP-2b + 8; MAP-2a), MAP-2b expressing exon 13 (MAP-2b + 13), and MAP-2c expressing exon 8 and exon 13 (MAP-2c + 8 + 13). The finding that MAP-2b + 8 is expressed in HFSC demonstrates for the first time the presence of MAP-2a in human fetal CNS. Immunocytochemical studies show that exon 8-specific antibody and exon 13-specific antibody stain independent and overlapping populations of neurons in the lumbar region of the HFSC. Antibody 13-immunopositive neurons have predominantly cytosolic staining, whereas in the antibody 8-immunoreactive neurons staining was observed in the cytosol, dendrites, and some synapses. The prenatal expression of MAP-2a, which has been used as a marker of synaptogenesis, not only demonstrates the presence of a mature MAP-2 isoform in HFSC, but suggests that MAP-2a is important during human fetal as well as postnatal synaptogenesis.

Embryonic and Fetal Development↗
PubMed1997

Distribution and subcellular localization of high-molecular-weight microtubule-associated protein-2 expressing exon 8 in brain and spinal cord.

The expression of high-molecular-weight (HMW) microtubule-associated protein-2 (MAP-2) expressing exon 8 (MAP-2 + 8) was examined by immunoblotting during rat brain development and in sections of human CNS. In rat brain, HMW MAP-2 + 8 expression was detected at embryonic day 21 and increased during postnatal development. In adult rats, HMW MAP-2 + 8 comigrated with MAP-2a. In human adult brain, HMW MAP-2 + 8 was expressed in select neuronal populations, including pyramidal neurons of layers III and V of the neocortex and parahippocampal cortex, pyramidal neurons in the endplate, CA2 and subiculum of the hippocampus, and the medium-sized neurons of the basal ganglia. In the cerebellum, a subpopulation of Golgi neurons in the internal granular cell layer and most Purkinje cells were also stained. In the spinal cord staining was observed in large neurons of the anterior horn. Staining was present in cell bodies and dendrites but not in axons. At the ultrastructural level, HMW MAP-2 + 8 immunoreactivity was observed on mitochondrial membranes and in postsynaptic densities (PSDs) of some asymmetric synapses in the midfrontal cortex and spinal cord. Immunoblots of proteins isolated from enriched mitochondrial and PSD fractions from adult human frontal lobe and rat brains confirmed the presence of HMW MAP-2 + 8. The presence of HMW MAP-2 + 8 in dendrites and in close proximity to PSDs supports a role in structural and functional attributes of select excitatory CNS synapses.

Amino Acid Sequence↗