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Results for “Protein Aggregation, Pathological”

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PubMed1992

Infection specific prion protein (PrP) accumulates on neuronal plasmalemma in scrapie infected mice.

Prion protein (PrP) is an abundant membrane-associated host protein which accumulates in abnormal, relatively protease-resistant forms in the brains of animals with scrapie and related diseases. Using correlative light and electron microscopy we determined the sites of subcellular localisation of PrP in mice infected with the 87V strain of scrapie. Disease specific accumulation of PrP was observed at light microscopy as amyloid plaques or as diffuse or granular staining within the neuropil, often clearly associated with individual neurons. Serial electron microscopical preparations were immunostained for PrP by the immunogold method. Gold particles were located on amyloid fibrils and on the plasmalemma of neurites at the periphery of plaques and in the neuropil, irrespective of the morphological form of PrP accumulation when viewed by light microscopy. This suggests that amyloid fibrils are formed following the accumulation and aggregation of sub-unit proteins at the plasmalemma and, furthermore, that normal PrP may be converted to its pathological form at this site.

Amyloid↗

PubMed1991

Spindle cell stromal tumors of gastrointestinal tract: a histological and immunohistochemical study.

Twenty-one consecutive cases of gastrointestinal spindle cell stromal tumors (SCSTs) were studied histologically and immunohistochemically. They consisted of 18 smooth muscle tumors, 2 neurilemmomas (schwannomas), and 1 unclassified malignant tumor designated as stromal sarcoma. Slender, spindle and wavy nuclei with palisading associated with peripheral tumor aggregation of lymphocytes are the pathological hallmarks of neurilemmoma. With peroxidase-antiperoxidase method, antibodies to Glial Fibrillary Acidic Protein (GFAP), Leu-7, S-100, desmin and HHF35 were applied. Antibodies to Leu-7 and GFAP could only be demonstrated in neurilemmomas (2 cases). Antibody to S-100 was observed strongly in 2 neurilemmomas and 1 stromal sarcoma, and focally in a leiomyoma, while the other SCSTs were negative. One neurilemmoma disclosed focal positivity of desmin. Six of 10 leiomyomas revealed varied degrees of positive staining of desmin and HHF35. One epithelioid leiomyoma, two leiomyosarcomas and five smooth muscle tumors of undetermined malignant potential (STUMP) disclosed no immunoreactivity. The study suggests that panel of immunostaining should be applied. Coexpression of GFAP, Leu-7 and S-100 as well as negative staining of HHF35 is characteristic of neurilemmoma. On the contrary, coexpression of desmin and HHF35 while negative for GFAP, S-100 and Leu-7 are suggestive of smooth muscle tumor. In poorly differentiated SCST, histological features and immunostains are always disappointing. Diagnosis of those tumors as stromal tumor is more appropriate or electron microscopic observation should be included for accurate classification.

Adult↗

PubMed1992

Amphotericin B treatment dissociates in vivo replication of the scrapie agent from PrP accumulation.

Scrapie and related animal and human disorders are neurodegenerative diseases characterized by the formation of a modified, partly proteinase-resistant protein (PrP) of the host, which tends to aggregate as amyloid fibrils and accumulate in the brain of infected individuals. There is a general consensus that the pathological form of PrP (PrPSc) is essential for the clinical appearance of the disease, but whether it is part of the scrapie agent or a by-product of viral infection is still controversial. Here we report that treatment of scrapie-infected hamsters with amphotericin B delays the accumulation in the brain of the proteinase-resistant portion of PrPSc by about 30 days without affecting scrapie replication. The consequence is that hamsters treated with amphotericin B developed clinical signs of disease later than infected controls. We argue that the proteinase-resistant portion of PrPSc is necessary for the development of the disease but that it is unlikely to be essential for scrapie replication.

Amphotericin B↗

PubMed1991

Abnormal Tau proteins in progressive supranuclear palsy. Similarities and differences with the neurofibrillary degeneration of the Alzheimer type.

We have previously shown that abnormal Tau species are produced during the neurofibrillary degeneration of the Alzheimer type. These abnormal Tau proteins consist of a characteristic triplet named Tau 55, Tau 64 and Tau 69 which are constantly found in Alzheimer's disease (AD) and Downs syndrome brain regions with tangles. To determine if abnormal Tau species are also produced in other neurodegenerative conditions where intraneuronal filamentous Tau aggregates are observed, we have undertaken an immuno-blot study of brain homogenates from patients with progressive supranuclear palsy (PSP), a neurological disorder characterized by the presence of tangles in subcortical and cortical brain areas. We show here that abnormal Tau species are produced in PSP but that they are different from those in AD. Indeed, although Tau 64 and 69 were present in PSP brain homogenates, possibly as the result of an abnormal phosphorylation as in AD, they were detected in smaller amounts (three times lower) than in AD. In addition Tau 55 was undetected by the immunological tools, such as the absorbed anti-PHF antisera, which specifically label the abnormal Tau proteins. Also the two-dimensional analysis revealed different isoelectric properties. Our results suggest that the production of abnormal Tau species is a very important event during all types of neurofibrillary degeneration. The differences in the pathological Tau-variant profile that were observed between PSP and AD possibly reflect different etiopathogenetic pathways and might explain the formation of different types of filamentous Tau aggregates.

Aged↗

PubMed1976

The significance of plasma lipoproteins on erythrocyte aggregation and sedimentation.

Increased erythrocyte aggregation can be induced by high concentrations of human lipoproteins. The dependence of aggregate formation on lipoprotein concentration was recorded by determination of erythrocyte sedimentation rate (ESR), by electrical measurement of the erythrocyte aggregation index (EAI) and by scanning electron microscopy. The lipoprotein concentrations necessary to induce a significantly increased ESR in an otherwise normal human plasma are much too high to be encountered in physiologic or even severe pathologic states. Therefore hyperlipoproteinaemia by itself cannot explain a raised ESR. In cases where the ESR is raised due to the presence of increased amounts of other erythrocyte aggregating plasma proteins (agglomerins), hyperlipoproteinaemia can contribute to a limited extent to the increase in ESR. The possible pathophysiological significance of the demonstrated erythrocyte aggregating capacity of human lipoproteins in a microvascular environment is noted.

Blood Sedimentation↗

PubMed1992

beta-Amyloid induces neuritic dystrophy in vitro: similarities with Alzheimer pathology.

beta-Amyloid protein, the major component of neuritic plaques found in Alzheimer's disease, has been implicated as a potential contributor to the disease's progressive neuropathology. We report that within a two day exposure to aggregates of synthetic beta-amyloid peptide, the neurites of cultured rat hippocampal neurons adopt a dystrophic appearance. Observed morphological changes in the neurites include beading, fragmentation, terminal swelling and tortuous growth patterns. The degenerative changes are similar to those observed in neurites associated with neuritic plaques, suggesting that beta-amyloid may induce the neuritic abnormalities of Alzheimer neuropathology.

Alzheimer Disease↗

PubMed1978

[Ultrastructural changes in the central nervous system of mice in tick-borne encephalitis].

Tick-borne encephalitis virus is localized in nerve cells and intracellular spaces. According to the nature of ultrastructural changes, the pathological process in nerve cells may be divided into three stages connected with the stages of virus reproduction. In the first stage, the protein-synthesizing systems of the cell are degraded. In the second stage specific virus inclusions form in the cell cytoplasm as aggregates of mature and immature virions alongside with destruction of ultrastructures and growth of smooth membranes. In the third stage degradation of neurons is accompanied by necrobiosis and discomplexation of the surrounding glial elements, processes, cells of the inflammatory infiltrate and capillary walls. A certain combination of nonspecific changes in organelles of various cells with viral inclusions makes the ultrastructural picture of the focus of lesions in tick-borne encephalitis sufficiently characteristic for differential pathological diagnosis.

Animals↗

PubMed1991

Receptors that activate platelets.

This review highlights the increasing knowledge of the biochemistry, pathology, and cell and molecular biology of platelet receptors. A receptor for ADP has been identified using the affinity label FSBA as aggregin, a 100-kDa membrane protein responsible for shape change, aggregation, and exposure of fibrinogen binding sites. A variety of putative receptors for collagen have been described, with GPIa/IIa and GPIV receiving the most attention recently. A thromboxane A2 receptor has been identified using receptor antagonists and photoaffinity labels. The alpha 2-adrenergic receptor has been cloned and expressed. The platelet thrombin receptor has been tentatively identified as GPIb. Following binding of thrombin to this receptor, activation of calpain occurs, with cleavage of aggregin leading to exposure of GPIIb/III alpha and platelet aggregation. Isolation, expression, or both of the ADP, collagen, and thrombin receptors as single gene products of the human platelet responsible for activation, and more complete understanding of stimulus-response coupling, should allow for greater specificity of drugs with selective therapeutic actions.

Animals↗

PubMed1992

Activation of neutrophil reactive-oxidant production by synovial fluid from patients with inflammatory joint disease. Soluble and insoluble immunoglobulin aggregates activate different pathways in primed and unprimed cells.

Cell-free synovial fluid from patients with rheumatoid arthritis stimulated the NADPH oxidase activity in human neutrophils, which reached a peak 15-20 min after addition. Insoluble immunoglobulin aggregates isolated from these fluids activated a similar pattern of oxidase activity. However, when synovial fluid was added to neutrophil suspensions which had been previously exposed to granulocyte-macrophage colony-stimulating factor, the stimulated oxidase activity was biphasic, in that an additional transient activity was observed which reached a peak within 5 min of addition. The additional neutrophil-stimulating activity could not be sedimented by centrifugation at 330,000 g-min, and only activated oxidase activity in neutrophils which had previously been primed. The neutrophil-stimulating activity in this soluble fraction was removed by Protein A affinity chromatography, and activity was recovered in eluates from this column. Thus activity in this soluble fraction from synovial fluid is attributed to the presence of soluble immunoglobulin aggregates. Whereas oxidase activity stimulated by the isoluble immunoglobulin aggregates was inhibited by staurosporine (and hence largely dependent on the activity of protein kinase C), the activity stimulated by the soluble immunoglobulin aggregates was staurosporine-insensitive. The soluble immunoglobulin aggregates were present at significantly higher levels in synovial fluids from patients with rheumatoid arthritis compared with those from other joint arthropathies. Thus rheumatoid synovial fluids possess heterogeneous immunoglobulin aggregates which activate neutrophils via distinct molecular pathways. As neutrophils within rheumatoid joints are primed, the soluble immunoglobulin aggregates are likely to be of importance in disease pathology.

Alkaloids↗

PubMed1992

Cytoskeletal changes in hepatocytes induced by Microcystis toxins and their relation to hyperphosphorylation of cell proteins.

The heptapeptide toxins produced by the blue-green alga (cyanobacterium) Microcystis aeruginosa are selectively hepatotoxic in mammals. The characteristic post-mortem pathology of the liver is extensive lobular disruption due to sinusoidal breakdown, leakage of blood into the tissue and hepatocyte disintegration. Isolated hepatocytes incubated with toxin show severe structural deformity and surface blebbing. This paper demonstrates the effects of Microcystis toxins on the contraction and aggregation of actin microfilaments, and on the relocation and breakdown of cytokeratin intermediate filaments, in cultured hepatocytes. Earlier work did not show changes in the assembly/disassembly of actin; however, this paper demonstrates the change in cytokeratin from intermediate filaments to distributed granules in the cytoplasm of toxin-affected cells. Acrylamide gel electrophoresis of cytoskeletal fractions from hepatocytes did not show changes in total cytokeratins; however, marked changes in the immunogenicity of cytokeratins at 52 and 58 kDa were seen on toxin exposure of cells. Measurement of 32P-phosphorylation of proteins in toxin-affected cells incubated with [32P]orthophosphate showed a dramatic increase compared to control incubations. This is in agreement with research elsewhere describing phosphatase inhibition in vitro by Microcystis toxins. The data indicate that phosphorylated cytokeratin is a major component of cytoplasmic fraction phosphorylated protein after toxin exposure to hepatocytes. It is concluded that the mechanism of Microcystis toxicity to the hepatocyte is through cytoskeletal damage leading to loss of cell morphology, cell to cell adhesion and finally cellular necrosis. The underlying biochemical lesion is likely to be phosphatase inhibition causing hyperphosphorylation of a number of hepatocyte proteins, including those cytokeratins responsible for microfilament orientation and intermediate filament integrity.

Actins↗

PubMed1992

Various cell types in human atherosclerotic lesions express ICAM-1. Further immunocytochemical and immunochemical studies employing monoclonal antibody 10F3.

The specificity of monoclonal antibody 10F3, generated to smooth muscle cells isolated from fetal human aorta, has been further explored in a series of biological, biochemical, and immunocytochemical studies. In the first assay, it was found that 10F3 could inhibit aggregation of phytohemagglutinin (PHA)-induced lymphocytes in a manner comparable to that of antibody RR1/1, an anti-intercellular adhesion molecule 1 (ICAM-1) monoclonal antibody. In immunoprecipitation experiments followed by one-dimensional gel electrophoresis, both 10F3 and RR1/1 immunoprecipitated 90 kd proteins, with results suggesting that the two antibodies recognized different epitopes of the same molecule. A series of immunocytochemical studies on human atherosclerotic lesions was performed; using single-labeling techniques, 10F3-positive cells were found in the vessel wall and in lesions of virtually all specimens of fatty streaks and fibrous plaques. Using double-labeling techniques, 10F3-positive macrophages and 10F3-positive smooth muscle cells were found; however, there were also a significant number of non-smooth muscle, nonmacrophage 10F3-positive cells. These studies demonstrate that 10F3 identifies ICAM-1, and that this protein is expressed on a variety of cell types in human atherosclerotic lesions. ICAM-1 may represent a developmentally regulated protein that is expressed in fetal but not adult mesenchymal cells, but can be re-expressed in pathologic processes such as atherosclerosis.

Adult↗

PubMed1992

Modulation of protein composition of nuclear lamina. Reduction of lamins B1 and B2 in livers of griseofulvin-treated mice.

Chronic griseofulvin (GF) intoxication of mice leads to severe alterations of the hepatocytic intermediate filament cytoskeleton similar to that found in alcoholic hepatitis in humans (i.e., derangement and diminution of the keratin filament network and appearance of cytoplasmic aggregates of keratin-containing material, termed Mallory bodies). To investigate eventual alterations of nuclear lamins under these pathologic situations monoclonal antibodies were produced. One of these, GL-35, was directed to lamin B1 and lamin B2. Immunofluorescence microscopy revealed in GF-treated livers, in comparison to normal mouse livers, a highly reduced immunoreaction for lamins B1 and B2, whereas the staining for lamins A and C was unchanged. This reduction of both B-type lamins occurred before detectable alterations of keratin filaments and was reversible after cessation of GF intoxication. A diminished content of both B-type lamins in relation to lamins A and C in GF-intoxicated livers was also revealed by analysis of isolated nuclear envelopes on two-dimensional gels. Moreover, there was a clear predominance of more acidic isoelectric variants of lamins B1 and B2. In contrast to the reduced amount of B-type lamin proteins no reduction in the concentration of the mRNA for lamin B1 was found. For lamin B2 even an increase of mRNA was detected in GF-treated livers. These results indicate that GF not only interferes with expression of the keratin intermediate filament skeleton of hepatocytes but also leads to selective alterations of the nuclear lamins, most likely by posttranslational modifications of intermediate filament proteins.

Animals↗

PubMed1990

[Paradoxical bleeding as a complication of the treatment of hemophilia with factor VIII and factor IX preparations].

Paradoxical bleedings are complications occurring under replacement therapy in haemophiliacs by disturbancies of the primary haemostasis. They have been observed during treatment with factor-VIII- and prothrombin-complex concentrates of long duration and in high dosage. Clinical complications, for example delayed wound healing as well as spontaneous bleedings into the skin and from the mucous membranes, have been observed in one quarter of haemophiliacs under substitution therapy. In one third of these patients pathological parameters of primary haemostasis (prolonged bleeding time, reduced retention, retraction, ADP- and collagen-induced aggregation and the platelet factor 3 release) were found out. The following mechanisms or substances may be the cause for these disturbancies: 1. fibrinogen and factor-VIII split products 2. high content of proteins predominantly fibrinogen and factor-VIII-related antigen 3. antigen-antibody reactions 4. development of inhibitors against the Willebrand factor. For treatment of the paradoxical bleedings freshly prepared cryoprecipitate, prednison and Etamsylatum have been used.

Anticoagulants↗

PubMed1992

Deposition of beta/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl-terminal fragment of the Alzheimer amyloid precursor in the brain.

The deposition of amyloid in senile plaques and along the walls of the cerebral vasculature is a characteristic feature of Alzheimer disease. The peptide comprising the carboxyl-terminal 100 amino acids of the beta-amyloid precursor protein (beta APP) has been shown to aggregate into amyloid-like fibrils in vitro and to be neurotoxic, suggesting that this fragment may play a role in the etiology of Alzheimer disease. To address this question, we expressed this carboxyl-terminal 100-amino acid peptide of beta APP in transgenic mice under the control of the brain dystrophin promoter. We used an antibody to the principal component of amyloid, beta/A4, to demonstrate cell-body and neuropil accumulation of beta/A4 immunoreactivity in the brains of 4- and 6-month-old transgenic mice. Only light cytoplasmic staining with this antibody was visible in control mice. In addition, immunocytochemical analysis of the brains with an antibody to the carboxyl terminus of beta APP revealed abnormal aggregation of this epitope of beta APP within vesicular structures in the cytoplasm and in abnormal-appearing neurites in the CA2/3 region of the hippocampus in transgenic mice, similar to its aggregation in the cells of Alzheimer disease brains. Thioflavin S histochemistry suggested accumulations of amyloid in the cerebrovasculature of transgenic mice with the highest expression of the beta APP-C100 transgene. These observations suggest that expression of abnormal carboxyl-terminal subfragments of beta APP in vivo may cause amyloidogenesis and specific neuropathology.

Amyloid beta-Protein Precursor↗

PubMed1991

Immunohistochemical localization of five classes of intermediate filament in a benign pelvic soft tissue tumor of rhabdoid appearance.

A benign pelvic soft tissue tumor from a 50-year-old woman was examined by immunohistochemistry and electron microscopy. The tumor cells had abundant eosinophilic cytoplasm with a hyaline appearance, which was filled with large aggregates of intermediate-sized filaments (IF). The cells were positively immunostained by antibodies against cytokeratin, vimentin, desmin, glial fibrillary acidic protein, and neurofilament proteins. This case represents an extreme example of the simultaneous expression of IF by neoplastic cells, and exemplifies the limited applicability of immunohistochemical detection of IF antigens for pathological diagnosis of neoplasms.

Female↗

PubMed1976

Red cell aggregation in blood flow. I. New methods of quantification.

The rheological behavior of normal and pathological red cell aggregates in viscometric flow (artificial flow in cone plate chamber) is studied by direct microscopy, (rheoscopy) viscometry and photometry. Marked differences between normal and pathological blood are measured in the microrheological properties of red cell aggregates; only discreet differences are measured by blood viscometry (macrorheology). Both in normal and abnormal blood, red cell aggregation is a reversible process in the presence of adequate shear forces; their respective influences on apparent blood viscosity at low rates of shear are complex functions of shear rate, shear time, hematocrit and plasma viscosities. Pathological red cell aggregation (RCA) forms more rapidly and extensively than normal RCA. The pathological aggregates frequently have a tendency to grow at low rates of shear and they are highly shear resistant.

Adolescent↗

PubMed1992

Functional and morphological changes in cultured neurons of rat cerebral cortex induced by long-term application of aluminum.

Aluminum is an environmental neurotoxin and a suspected risk factor for Alzheimer's disease. The neurotoxicity of aluminum on cultured neurons of rat cerebral cortex was investigated using an assay system for synapse formation and immunohistochemistry. The frequency of spontaneous oscillations of intracellular Ca2+, which is correlated to the number of synapses, was decreased after exposure to 100 microM of aluminum chloride for 22 days. Long-term application of aluminum (48 days) caused aggregation of cell bodies and fasciculation of processes. Processes and cell bodies were strongly stained by antibody to tau protein, which is one of the main components of Alzheimer's neurofibrillary tangles. It is suggested that the characteristics of the degeneration of cultured neurons induced by aluminum show some similarities to the pathology observed in brains with Alzheimer's disease.

Aluminum↗

PubMed1992

The mechanism of Z alpha 1-antitrypsin accumulation in the liver.

Most northern Europeans have only the normal M form of the plasma protease inhibitor alpha 1-antitrypsin, but some 4% are heterozygotes for the Z deficiency variant. For reasons that have not been well-understood, the Z mutation results in a blockage in the final stage of processing of antitrypsin in the liver such that in the Z homozygote only 15% of the protein is secreted into the plasma. The 85% of the alpha 1-antitrypsin that is not secreted accumulates in the endoplasmic reticulum of the hepatocyte; much of it is degraded but the remainder aggregates to form insoluble intracellular inclusions. These inclusions are associated with hepatocellular damage, and 10% of newborn Z homozygotes develop liver disease which often leads to a fatal childhood cirrhosis. Here we demonstrate the molecular pathology underlying this accumulation and describe how the Z mutation in antitrypsin results in a unique molecular interaction between the reactive centre loop of one molecule and the gap in the A-sheet of another. This loop-sheet polymerization of Z antitrypsin occurs spontaneously at 37 degrees C and is completely blocked by the insertion of a specific peptide into the A-sheet of the antitrypsin molecule. Z antitrypsin polymerized in vitro has identical properties and ultrastructure to the inclusions isolated from hepatocytes of a Z homozygote. The concentration and temperature dependence of this loop-sheet polymerization has implications for the management of the liver disease of the newborn Z homozygote.

Circular Dichroism↗