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Results for “Protein Aggregation, Pathological”

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PubMed2005

Effects of different anti-tau antibodies on tau fibrillogenesis: RTA-1 and RTA-2 counteract tau aggregation.

Tau is the major antigenic component of neurofibrillary pathology in tauopathy, including Alzheimer's disease. Although conversion of soluble tau to an insoluble polymerized fibrillar form is a key factor in the pathogenesis of tauopathy, the mechanism of the change is unclear and no inhibitors of fibril formation are available. Monoclonal antibodies against the 1st or 2nd repeat of the microtubule binding domain, but not the C-terminal 16 residues, completely inhibited tau aggregation into PHF. Furthermore, they did not inhibit tau-induced tubulin assembly. Thus, they are useful to investigate tau protein conversion and will be useful therapeutic lead materials.

Amino Acid Sequence↗

PubMed2003

Glycoprotein Ib-IX-mediated activation of integrin alpha(IIb)beta(3): effects of receptor clustering and von Willebrand factor adhesion.

The interaction between the platelet glycoprotein (GP) Ib-IX complex and von Willebrand factor (VWF) initiates both hemostasis and pathological thrombosis. This interaction is not only the first adhesive event of platelets at sites of vessel injury, but also facilitates fibrinogen binding to alpha(IIb)beta(3), which subsequently results in platelet aggregation. Since it has been suggested that GP Ib-IX clustering may promote platelet activation, we investigated the effect of such clustering on both VWF-GP Ib-IX and fibrinogen-alpha(IIb)beta(3) bonds using optical tweezers. In our system, fusion of tandem repeats of FK506-binding protein (FKBP) to the cytoplasmic tail of the GP IX subunit of the GP Ib-IX complex allowed subsequent receptor clustering within the plasma membrane by the bivalent, cell-permeant small molecule ligand AP20187. We measured binding forces between polystyrene beads coated with either plasma-derived VWF or the VWF A1 domain and GP Ib-IX(FKBP)2, and those between fibrinogen-coated beads and alpha(IIb)beta(3) expressed on Chinese hamster ovary cells. The minimal detachment force between GP Ib-IX(FKBP)(2) and A1 or plasma-derived VWF doubled after AP20187 was added. The binding force between immobilized fibrinogen and alpha(IIb)beta(3) was not changed by the clustering agent; however, the strength of single fibrinogen-alpha(IIb)beta(3) bonds increased significantly after ligation of GP Ib-IX(FKBP)(2) by A1. These results demonstrate that GP Ib-IX clustering increases the overall strength of its interaction with VWF. Furthermore, signals from GP Ib-IX can activate alpha(IIb)beta(3), thereby increasing the strength of its interaction with fibrinogen.

Adhesiveness↗

PubMed2001

Cardiovascular properties of yangambin, a lignan isolated from Brazilian plants.

Yangambin was initially selected from a number of lignans isolated from Brazilian plants for its ability to antagonize Platelet-Activating Factor (PAF, 1-O-hexadecyl-2-acetyl- sn-glyceryl-3-phosphorylcholine)-induced biological effects. Subsequently it was shown that, besides its antagonistic properties at PAF receptors, yangambin also prevents the cardiovascular collapse observed during anaphylactic and endotoxic/septic shocks, as well as the vascular and cardiac hyporesponsiveness to catecholamines in endotoxic shock. It is suggested that this naturally occurring compound could be of potential interest in the adjunctive management of the above mentioned pathologies. In the present article, we review the main studies investigating the pharmacological properties of yangambin related to the cardiovascular function.

Anaphylaxis↗

PubMed2003

Microtubule-associated tau protein positive neuronal and glial inclusions in ALS.

BACKGROUND: The authors compared tau protein deposition in the frontal cortex of patients with cognitive impairment of amyotrophic lateral sclerosis (ALSci) (n = 6), cognitively intact patients with ALS (n = 6), and age-matched controls (n = 6) in order to determine the pathologic substrate of ALSci. METHODS: Archival paraffin-embedded tissue was examined using Gallyas staining and immunostaining for tau-1 (phosphorylation-dependent tau epitope), tau-2 (phosphorylation independent), Alzheimer-specific tau phosphoepitopes (AT 8; ser(396) phosphorylation), beta-amyloid, glial fibrillary acid protein, SMI 31 (recognizing phosphorylated NFH), alpha-synuclein, or ubiquitin. RESULTS: Tau immunoreactive astrocytic and dense neuronal inclusions were found in both ALS and ALSci, although to a greater extent in ALSci. Superficial linear spongiosis and Gallyas-positive intraneuronal aggregates, immunoreactive with tau-1 and AT 8 but rarely to ser(396) tau, were unique to ALSci. Dense extracellular aggregates were observed by both Gallyas staining and tau-1 immunostaining. Tufted degenerating astrocytes containing tau-1 and AT 8 immunoreactive aggregates and, rarely, dense Gallyas positive neuritic plaques immunoreactive with tau-1 and AT 8, but not with ser(396) tau or beta-amyloid, were observed in ALSci. Tau positive glial coiled bodies were observed in the deep cortical layers and adjacent subcortical white matter in ALSci. Although 3R and 4R tau mRNA isoforms were expressed to similar levels in the frontal cortex of all cases, the total amount of tau mRNA was increased in both ALS and ALSci. Both gray and white matter soluble tau protein expression was similar among control, ALS, and ALSci cases. CONCLUSIONS: Cognitive dysfunction in ALS may reflect abnormal tau protein metabolism.

Aged↗

PubMed2006

Impaired NH2-terminal processing of human proislet amyloid polypeptide by the prohormone convertase PC2 leads to amyloid formation and cell death.

Islet amyloid, formed by aggregation of islet amyloid polypeptide (IAPP; amylin), is a pathological characteristic of the pancreas in type 2 diabetes and may contribute to the progressive loss of beta-cells in this disease. We tested the hypothesis that impaired processing of the IAPP precursor proIAPP contributes to amyloid formation and cell death. GH3 cells lacking the prohormone convertase 1/3 (PC1/3) and IAPP and with very low levels of prohormone convertase 2 (PC2) were transduced with adenovirus (Ad) expressing human or rat (control) proIAPP linked to green fluorescent protein, with or without Ad-PC2 or Ad-PC1/3. Expression of human proIAPP increased the number of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells 96 h after transduction (+hIAPP 8.7 +/- 0.4% vs. control 3.0 +/- 0.4%; P < 0.05). COOH-terminal processing of human proIAPP by PC1/3 increased (hIAPP+PC1/3 10.4 +/- 0.7%; P < 0.05), whereas NH(2)-terminal processing of proIAPP by addition of PC2 markedly decreased (hIAPP+PC2 5.5 +/- 0.5%; P < 0.05) the number of apoptotic GH3 cells. Islets from mice lacking PC2 and with beta-cell expression of human proIAPP (hIAPP(+/+)/PC2(-/-)) developed amyloid associated with beta-cell death during 2-week culture. Rescue of PC2 expression by ex vivo transduction with Ad-PC2 restored NH(2)-terminal processing to mature IAPP and decreased both the extent of amyloid formation and the number of TUNEL-positive cells (-PC2 26.5 +/- 4.1% vs. +PC2 16.1 +/- 4.3%; P < 0.05). These findings suggest that impaired NH(2)-terminal processing of proIAPP leads to amyloid formation and cell death and that accumulation of the NH(2)-terminally extended human proIAPP intermediate may be a critical initiating step in amyloid formation.

Adenoviridae↗

PubMed2004

[Intracellular signaling pathways, apoptosis and neurodegenerative diseases].

Progressive regional loss of neurons underlies the irreversible pathology of various neurodegenerative brain diseases. In mature organisms, neurons die either by necrosis or apoptosis. Apoptotic neuronal cell death is the cardinal feature of aging and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases, but its mechanisms remain unsolved. Cysteine proteases like caspases are known to be critical effectors in the central nervous system cellular apoptosis. More recently, the calcium-dependent protease, calpains, have been implicated in cellular apoptotic processes. Moreover, for most neurodegenerative diseases, aggregation of full length or truncated proteins is central but the mechanisms involved still remain a mystery. With the identification of the mechanisms which promote or prevent cell apoptosis, new approaches for preventing and treating neurodegenerative disorders could be proposed. This article reviews our understanding of intracellular signaling pathways which lead to apoptosis in the nervous system, concentrating on its possible roles in chronic neurodegenerative disorders.

Aged↗

PubMed1991

The distinct pathobiology of sickle cell-hemoglobin C disease. Therapeutic implications.

The data available clearly establish that the hyperconcentration of hemoglobin C and S inside SC cells is the main and driving mechanism for the pathologic behavior of these cells. It facilitates the polymerization of Hb S, but it also favors the tendency of Hb C to induce the formation of crystals and aggregates, abnormal morphologic shapes, and abnormally dense reticulocytes, through a particularly active K:Cl cotransport. Why these cells are endowed with a particularly active K:Cl cotransport is still a mystery; it is disproportionate with the extent of the hemolysis and the number of young cells. Is there an abnormal interaction between Hb C and the K:Cl cotransport protein in the inner aspect of the membrane? Are there abnormal interactions between Hb C and the other transport mechanisms that balance the shrinking capacity of K:Cl cotransport (as Na/H exchange)? Only future work will tell. In any case, SC disease is unique among the hemoglobinopathies in that a single intervention could correct all abnormalities: the restitution of the normal MCHC, as proven experimentally by Fabry et al. Hence, effort should be centered on looking for compounds that increase red cell volume, because in SC cells, increases in volume will not distort the cell, but restore it to the normal red cell volume and the normal red cell shape. This luxury is not available for cells with normal MCHC (the majority of the red cells in SS blood), because increasing their volume will progressively turn them into spheres, a rheologically disadvantaged shape.

Animals↗

PubMed2006

The receptor for advanced glycation end products and its ligands: a new inflammatory pathway in lung disease?

The binding of the receptor for advanced glycation end products (RAGE) with its ligands begins a sustained period of cellular activation and inflammatory signal amplification in different tissues and diseases. This binding could represent an as yet uninvestigated pathway of inflammatory reaction in the lung, where the presence of the receptor has been largely documented and advanced glycation end products (AGEs) are produced by nonenzymatic glycation and oxidation of proteins and lipids, driven by smoke and pollutants exposure or inflammatory stress. We immunohistochemically assessed the expression of RAGE and of its major proinflammatory ligands, N-epsilon-carboxy-methyl-lysine, S100B and S-100A12 in normal lung and in non-neoplastic lung disorders including smoke-related airway disease, granulomatous inflammation, postobstructive damage and usual interstitial pneumonia. In normal lung low expression of the receptor was observed in bronchiolar epithelia, type II pneumocytes, macrophages and some endothelia. S100A12 and S100B were expressed, respectively, in granulocytes and in dendritic cells. Carboxy-methyl-lysine was present in bronchiolar epithelia and macrophages. In all pathological conditions associated with inflammation and lung damage overexpression of both the receptor and of AGEs was observed in bronchiolar epithelia, type II alveolar pneumocytes, alveolar macrophages and endothelia. RAGE overexpression was more evident in epithelia associated with inflammatory cell aggregates. Fibroblasts in usual interstitial pneumonia expressed both the receptor and AGEs. The number of S100A12 and S100B immunoreactive inflammatory cells was variable. S100A12 was also expressed in mononuclear inflammatory cells and in activated epithelia. The activation of the inflammatory pathway controlled by the RAGE is not specific of a single lung disease, however, it may be relevant as a nonspecific pathway of sustained inflammation in lung tissue, and on this basis therapeutic approaches based on receptor blockage can be envisaged.

Airway Obstruction↗

PubMed1983

Iron loading in the liver of parasitic adult lampreys, Petromyzon marinus L.

Electron microscopic and histochemical procedures were used to describe iron loading in the normal liver of parasitic adult sea lampreys. Petromyzon marinus L. Ferric iron is present in large quantities as ferritin in the cytoplasmic matrix, in hemosiderin granules, and in large vacuoles of hepatocytes. Ferritin is also found in the lateral intercellular space, in the perivascular space, and in the sinusoidal lumen. Large crystals in the cytoplasmic and nuclear matrices of some hepatocytes likely represent excessive aggregations of ferritin molecules. Ferrous iron is localized at the lateral cell membrane and vacuolar membranes of hepatocytes. Iron accumulation is less significant in Kupffer cells which are present in small numbers. The relationship of iron loading in the adult lamprey liver to the sanguivorous diet, the rate of erythrophagocytosis, the absence of bile ducts and canaliculi, and the nature of the iron-binding proteins in the plasma are considered. Emphasis is placed on the similarity of the above morphological findings to those resulting from experimentally induced and pathological states of iron loading in other vertebrates, and on the potential use of the lamprey as a model for studying iron loading in the vertebrate liver.

Animals↗

PubMed2002

Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases.

Intracytoplasmic inclusions composed of alpha-synuclein (alpha-syn) are characteristic of neurodegenerative Lewy body disorders. Using novel monoclonal antibodies raised against altered alpha-syn, we uncovered an unprecedented and extensive burden of alpha-syn pathology in the striatum of Lewy body disorders. The highest density of striatal pathology was observed in patients with a combination of Alzheimer's disease and dementia with Lewy bodies or pure dementia with Lewy bodies, and these alpha-syn aggregates may contribute to the parkinsonism seen in these disorders.

Antibodies, Monoclonal↗

PubMed2000

Structure of abnormal molecular assemblies (collagen VI) associated with human full thickness macular holes.

Transversely banded deposits with an approximately 100-nm periodicity have been seen in association with a number of eye pathologies (e.g., age-related macular degeneration). Recently such aggregates have also been discovered in the cortical vitreous of a patient suffering from full thickness macular holes. The aggregates in the vitreous were of sufficient size and regularity for us to attempt 3D ultrastructural studies in the electron microscope. The molecules forming this aggregate pack in a centered tetragonal unit cell of dimensions approximately 26 x 26 x 180 nm. A real-space (r-weighted back projection) 3D reconstruction was computed. The aggregate is discussed in terms of its possible protein constituents. Collagen VI has been singled out as the most likely protein to form the aggregate. Two alternative models for the molecular packing are proposed, comprising aggregates of molecular tetramers or octamers. Understanding the structure of these abnormal banded deposits in the eye should help to throw light on the pathophysiological mechanisms of the diseases, including age-related macular degeneration, in which they occur.

Bruch Membrane↗

PubMed2001

Aberrant expression of cell-cycle regulatory proteins in human mesenchymal neoplasia.

We previously demonstrated that approximately one-half of soft-tissue sarcomas were devoid of either pRB, the product of the retinoblastoma gene, or 16, the product of the MTS1/CDKN2 gene, while a smaller subset of aggressive mesenchymal tumors without metastatic potential did not express RB by immunohistochemistry. We now studied the expression of two additional important cell-cycle regulators, namely cyclin D1 and p53, in the same cohort of high- and low-grade lesions. In the aggregate, our data provide a comprehensive overview of the importance of cell-cycle deregulation in mesenchymal neoplasia. Paraffin sections of 58 sarcomas and 23 soft-tissue tumors of low malignant potential (STT-LMP) were reacted with monoclonal antibodies against cyclin D1 and p53, using optimized immunohistochemical staining protocols. The staining data were correlated with expression of pRB and p15 and with a variety of pathologic parameters. A total of 33 of 58 sarcomas (57%) and 9 of 23 STT-LMP (39%) overexpressed p53. Fourteen sarcomas (24%) and 4 STT-LMP (17%) overexpressed cyclin D1. There was no correlation between expression of these two genes and histologic tumor type or grade. Loss of RB and loss of p16 or overexpression of cyclin D1 were mutually exclusive events. Considering all four cell-cycle regulators, sarcomas had a significantly higher abnormality rate than did STT-LMP (P < .005). Only 10% of the sarcomas but 39% of STT-LMP showed normal expression of all four gene products. Based on our findings, overexpression of cyclin D1 and (presumably mutant) p53 appear to be among the most common molecular alterations in human mesenchymal neoplasia, and abrogation of cell-cycle control is observed in the great majority of sarcomas; it is present significantly less frequently in low-grade lesions.

Cell Cycle↗

PubMed1994

Leiomyosarcoma of the vulva: report of a case.

A 52-year-old female presented with a progressively enlarging vulvar mass. Pathological evaluation revealed a high-grade vulvar leiomyosarcoma. Immunohistochemical and ultrastructural studies were performed to support the diagnosis. In an effort to better understand the biology of this tumor additional immunohistochemical studies for the protein product of p53 tumor suppressor gene and estrogen receptor expression by tumor cells, as well as the type of immune cells infiltrating the tumor were performed. Tumor cells showed an overexpression of p53 protein and were estrogen receptor-positive. Macrophages and T and B lymphocytes infiltrated the tumor in moderate numbers with occasional lymphoid aggregate formation. This study is the first attempt to better understand the biology of these tumors.

B-Lymphocytes↗

PubMed2006

Relation of hippocampal phospho-SAPK/JNK granules in Alzheimer's disease and tauopathies to granulovacuolar degeneration bodies.

Protein misfolding is a distinguishing feature of a number of neurodegenerative diseases. Accumulation of misfolded protein often results in cellular lesions, the location of lesions correlating with the nature of symptoms. Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD) and Pick's Disease (PiD) all present with pathological lesions containing hyperphosphorylated filamentous tau protein; however, the location and type of lesion varies. In addition, granulovacuolar degeneration (GVD) bodies have been reported within hippocampal pyramidal neurons in AD, PSP, CBD and PiD tissue. GVDs are defined as electron-dense granules within double membrane-bound cytoplasmic vacuoles. We have previously reported that the phosphorylated form of stress-activated protein kinase/c-Jun N-terminal kinase (p-SAPK/JNK) accumulates in granules within hippocampal pyramidal cell bodies in AD tissue at the time that hyperphosphorylated tau begins to aggregate into early-stage NFTs. We now report that p-SAPK/JNK granules are found within the hippocampal CA1 region of PSP, CBD and PiD cases as well and that these granules are likely GVD bodies. Quantitatively, p-SAPK/JNK granules and GVDs are found in comparable numbers of CA1 cells. Within cells, p-SAPK/JNK granules are distributed throughout the cytoplasm in a manner similar to the distribution of GVDs and a subset of granules co-localize with GVD markers. Ultrastructurally, p-SAPK/JNK granules are located in large cytoplasmic vacuoles, thereby fitting the definition of a GVD body. With the implication of granular p-SAPK/JNK as a marker of GVDs, our study strongly suggests that a heterogeneous group of proteins form GVDs. The mechanism of GVD formation is therefore an interesting one, and is likely separate and distinct from the mechanism of tau inclusion formation.

Aged↗

PubMed2004

Protein quality control in Alzheimer's disease by the ubiquitin proteasome system.

The ubiquitin proteasome system (UPS) is the major protein quality control system in eukaryotic cells. Many neurodegenerative diseases are characterized by aggregates and inclusions of aberrant proteins, implying a sub-optimal functioning or defective UPS. The last few years have seen increasing evidence for the involvement of the UPS in neurodegenerative disorders, including Alzheimer's disease (AD). Notably, decreases in proteasome activity were detected in several cortical areas in AD patients. In addition, proteins that accumulate in the classical hallmarks of AD were linked to UPS function. This review specifically discusses the involvement of the UPS in AD pathogenesis. First, a detailed overview of the UPS is presented, after which AD pathology and its relation to the UPS is discussed.

Aging↗

PubMed2001

Characterization of human villous and extravillous trophoblasts isolated from first trimester placenta.

Trophoblasts of the human placenta differentiate along two pathways to give either extravillous cytotrophoblasts (EVCT) with invasive properties and that are implicated in the implantation process, or villous cytotrophoblasts (VCT) that by cell fusion form multinucleated syncytiotrophoblasts. We report the first isolation and purification of these two cell types from the same chorionic villi of first trimester human placenta. We also studied their differentiation in vitro. Electron microscopy showed that in contrast to VCT, EVCT had no microvilli but contained large fibrinoid inclusions. EVCT cultures required a matrix to invade, and as previously established, VCT cultured on plastic dishes aggregated and fused to form syncytiotrophoblasts. These differentiation processes were characterized by a particular pattern of gene expression as assessed by real-time PCR and confirmed by immunocytochemical analysis of the corresponding proteins. EVCT cultured in vitro expressed high levels of HLA-G, c-erbB2, human placental lactogen, and very little human chorionic gonadotropin. Interestingly, TGFbeta2 was a marker of EVCT in vitro and in situ. These data offer a new tool for cell biologists to study the molecular mechanisms involved in human placental development and its pathology.

Cell Differentiation↗

PubMed1995

Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide.

Paired helical filament (PHF) tau is the principal component of neurofibrillary tangles, a characteristic feature of the neurodegenerative pathology in Alzheimer's disease (AD). Post-translational modification of tau, especially phosphorylation, has been considered a major factor in aggregation and diminished microtubule interactions of PHF-tau. Recently, it has been recognized that PHF-tau is also subject to non-enzymatic glycation, with formation of advanced glycation end products (AGEs). We now show that as a consequence of glycation, PHF-tau from AD and AGE-tau generate oxygen free radicals, thereby activating transcription via nuclear factor-kappa B, increasing amyloid beta-protein precursor and release of approximately 4 kD amyloid beta-peptides. These data provide insight into how PHF-tau disturbs neuronal function, and add to a growing body of evidence that oxidant stress contributes to the pathogenesis of AD.

Alzheimer Disease↗

PubMed2000

Hemostatic protease receptors and endothelial cell function: insights from gene targeting in mice.

Hemostasis constitutes a major defense system of our body that maintains blood flow in the circulation and prevents life-threatening blood loss. The endothelium plays a crucial dynamic role as a protective interface between blood and the underlying tissues during this process. Following vessel wall injury with initial platelet adhesion and aggregation to exposed subendothelial extracellular matrix, the initiation, amplification, and control of hemostasis depend on structurally unrelated membrane-associated receptors for blood coagulation proteases including tissue factor, G protein-coupled protease-activatable receptors, thrombomodulin, or protein C receptor. In addition to their regulatory role in hemostasis, the respective (pro-)enzyme ligands such as factors VIIa and Xa, thrombin, and protein C mediate specific signaling pathways in vascular cells related to migration, proliferation, or adhesion. The functional importance of these receptors beyond hemostasis has been manifested by various lethal or pathological phenotypes in knock-out mice. These protease receptors thereby provide important molecular links in the vascular system and serve to integrate hemostasis with endothelial cell functions that are relevant for the (patho-) physiological responses to inflammatory challenges, injury, or infection.

Animals↗