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Results for “Protein Aggregation, Pathological”

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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↗

PubMed1993

Transgenic animal models for Alzheimer's disease.

The neuropathology of Alzheimer's disease is characterized by the deposition of abnormal protein aggregates. The main constituent of the deposition is beta-amyloid protein. A seminal role of this protein is supported by the discovery of point mutations in the gene of its precursor protein in certain forms of familial Alzheimer's disease. In vitro (cultured neuronal cells), overexpression of the precursor protein or a part of the precursor leads to degeneration of neurons, suggesting neurotoxicity of its derivatives. At this time, all of the reported transgenic mice bearing DNA construct for the precursor or a part of the precursor, however, have not developed convincing pathological changes similar to what is observed in patients with Alzheimer's disease. This interesting discrepancy between in vitro and in vivo suggests suppressors in vivo which ameliorate beta-amyloid precursor protein derivative-mediated neurotoxicity.

Alzheimer Disease↗

PubMed2004

Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain.

Multiple lines of evidence implicate beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD), but the mechanisms whereby Abeta is involved remain unclear. Addition of Abeta to the extracellular space can be neurotoxic. Intraneuronal Abeta42 accumulation is also associated with neurodegeneration. We reported previously that in Tg2576 amyloid precursor protein mutant transgenic mice, brain Abeta42 localized by immunoelectron microscopy to, and accumulated with aging in, the outer membranes of multivesicular bodies, especially in neuronal processes and synaptic compartments. We now demonstrate that primary neurons from Tg2576 mice recapitulate the in vivo localization and accumulation of Abeta42 with time in culture. Furthermore, we demonstrate that Abeta42 aggregates into oligomers within endosomal vesicles and along microtubules of neuronal processes, both in Tg2576 neurons with time in culture and in Tg2576 and human AD brain. These Abeta42 oligomer accumulations are associated with pathological alterations within processes and synaptic compartments in Tg2576 mouse and human AD brains.

Adult↗

PubMed1999

[Experimental study on the early liver injury and expression of TNF-alpha mRNA after burns complicated by endotoxemia].

OBJECTIVE: To observe the distribution and cell localization of TNF-alpha mRNA and its protein and study their role on pathogenesis of liver injury in rats. METHODS: An animal model in which rats were subjected to 20% TBSA III degree burns combined with intraperitoneal injection of lipopolysaccharide (LPS) was used for this experiment. The changes in the hepatic morphology, functions and TNF-alpha content in the serum and the expression, localization of liver TNF-alpha and TNF-alpha mRNA were determined with LM and EM, quantitative analysis, immunohistochemistry(IHC) and in situ hybridization (ISH). RESULTS: It was showed that there were sinusoid reaction, KCs activation and degeneration, necrosis of HCs, and platelets aggregation, fibrin deposition and PMNs attachment in sinusoid. The activity of ALT was obviously elevated and the content of ALB was slightly lowered. The contents of TNF-alpha in serum showed the peak values at 3 h. TNF-alpha was mainly localized in sinusoid endothelial cells(SECs), Kupffer cells (KCs) and TNF-alpha mRNA was mainly distributed in KCs, polymorphonuclear neutrophils (PMNs) and macrophages(MPs). CONCLUSION: The results suggest that the expression and localization of TNF-alpha mRNA and its protein are in agreement with the pathological changes of liver injury. TNF-alpha is one of the key cytokines in pathogenesis of liver injury in rats after burns complicated by endotoxemia.

Animals↗

PubMed2003

Pathobiology of primary mediastinal B-cell lymphoma.

Controversy still exists over the response to therapy and prognosis of patients with primary mediastinal B-cell lymphoma (PMBL). Recent data from the International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B (methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) chemotherapy regimen followed by radiotherapy may be a better induction strategy than other previously used treatments. Although the pathobiology of PMBL has been widely studied, its precise histology, phenotype, and molecular characteristics are still not clear. To date, phenotypic analysis has revealed the following phenotype: positivity for CD45 and CD20, but negativity for CD3, CD10, CD21, Class I/II major histocompatibility antigens, and a variety of other immunohistochemical markers. CD79a is generally detected, despite an absence of surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic large cell lymphoma. BCL-2 protein is usually expressed but there are few data describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains in segments of chromosome 9p, including amplification of the REL proto-oncogene and the tyrosine kinase gene JAK2. Other molecular findings include: C-myc mutations or rearrangements, p53 mutations, IgV(H), gene mutations, and bcl-2 and mal over-expression. bcl-6 mutations and bcl-2 gene rearrangements are generally absent, suggesting that PMBL is of pre-germinal center (GC) origin. However, two recent reports show isotype-switched Ig genes with a high frequency of somatic hypermutations as well as variants in the 5' noncoding region of the bcl-6 gene. The IELSG collected 137 PMBL cases for extensive pathologic review. Histologically, the lymphomatous growth was predominantly diffuse with sclerosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. Molecular analysis was performed on 40 cases and showed novel findings. More than half of the cases displayed bcl-6 gene mutations, which usually occurred together with functioning somatic IgV(H) gene mutations, and BCL-6 and/or MUM1/IRF4 expression. The present study supports the concept that PBML is derived from activated GC or post-germinal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective Ig production despite the expression of Oct-2, BOB.1, and PU.1 transcription factors, and a lack of IgV(H) gene crippling mutations.

Diagnosis, Differential↗

PubMed2000

Relationship of cytokeratin 20 and CD44 protein expression with WHO/ISUP grade in pTa and pT1 papillary urothelial neoplasia.

The aim of this study was to assess the relationship of immunoreactivity of cytokeratin 20 (CK20) and CD44 across the spectrum of urothelial neoplasia using the WHO/ISUP consensus classification. A total of 120 papillary urothelial pTa and pT1 tumors (8 papillomas, 8 neoplasms of low malignant potential, and 42 low-grade and 62 high-grade carcinomas) were immunostained by using CK20 and CD44 antibodies. The relationships of tumor grade, pathologic stage, recurrences, and progression in stage with CK20 and CD44 immunoreactivity were assessed. WHO/ISUP grade correlated with tumor stage (P < 0.005), recurrence (P = 0.02), and progression in stage (P = 0.031). Normal urothelium showed CK20 immunoreactivity restricted to a few umbrella cells. Expression of CD44 in normal urothelium was restricted to the basal cell layer. Loss of CD44 immunoreactivity and increasing CK20 positivity were significantly associated with increasing tumor grade and stage (P < 0.005). An inverse relationship was observed in the staining patterns of CK20 and CD44 within individual cases, as well as in the aggregate data, with 79.2% of tumors with CD44 loss showing CK20 positivity (P < 0.001). In conclusion, CK20 and CD44 immunoreactivity are significantly related to the WHO/ISUP grade and to each other, and our data suggest their potential combined utility in predicting biologic behavior in patients with papillary urothelial pTa and pT1 neoplasms.

Adult↗

PubMed2000

Vascular protease receptors: integrating haemostasis and endothelial cell functions.

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

Animals↗

PubMed2006

Beta-amyloid treatment of two complementary P301L tau-expressing Alzheimer's disease models reveals similar deregulated cellular processes.

Alzheimer's disease (AD) is characterized by Abeta peptide-containing plaques and tau-containing neurofibrillary tangles (NFTs). Both pathologies have been combined by crossing Abeta plaque-forming APP mutant mice with NFT-forming P301L tau mutant mice or by stereotaxically injecting beta-amyloid peptide 1-42 (Abeta42) into brains of P301L tau mutant mice. In cell culture, Abeta42 induces filamentous tau aggregates. To understand which processes are disrupted by Abeta42 in the presence of tau aggregates, we applied comparative proteomics to Abeta42-treated P301L tau-expressing neuroblastoma cells and the amygdala of P301L tau transgenic mice stereotaxically injected with Abeta42. Remarkably, a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. We also identified model-specific effects of Abeta42 treatment such as differences in cell signaling proteins in the cellular model and of cytoskeletal and synapse associated proteins in the amygdala. By Western blotting (WB) and immunohistochemistry (IHC), we were able to show that 72% of the tested candidates were altered in human AD brain with a major emphasis on stress-related unfolded protein responsive candidates. These data highlight these processes as potentially important initiators in the Abeta42-mediated pathogenic cascade in AD and further support the role of unfolded proteins in the course of AD.

Alzheimer Disease↗

PubMed2004

Immunoglobulin kappa light chain and its amyloidogenic mutants: a molecular dynamics study.

AL amyloidosis and LCDD are pathological conditions caused by extracellural deposition of monoclonal Ig light chain variable domains. In the former case, deposits have a form of amyloid fibrils, in the latter, amorphous aggregates. 1REI kappa light chain variable domain and its two point mutants, R61N and D82I, were chosen for the analysis in this work. Wild 1REI does not create deposits in vitro, while R61N aggregates as amyloid fibrils and D82I creates amorphous aggregates. Both mutated residues create a conserved salt bridge; thus, substitution of any of them should decrease V(L) domain stability. For these three proteins, 5 ns MD simulations were conducted in temperatures of 300 K and 400 K, with protonated and unprotonated acidic residues, mimicking acidic and neutral experimental pH conditions (3 sets: N300, N400, and A400). The analysis of trajectories focused on characterization of changes in conformational behavior and stability of Ig kappa light chain variable domain caused by single aminoacid substitutions that were experimentally proved to enhance aggregation propensity, both in the form of amyloid and amorphous aggregates. Residue D82 turns out to be involved not only in R61-D82 but also in K45-D82 interaction, which was not observed in the X-ray structure, but frequently populated simulations of 1REI. The substitution D82I excludes both interactions, resulting in substantial destabilization (i.e., easier aggregation). Examination of behavior of edge regions of V(L) beta-sandwich reveals significant alterations in D82I mutant compared to wild 1REI, while relatively small changes occur in R61N. This suggests that mild and slow destabilization is the reason of the conversion of V(L) to partially folded amyloidogenic intermediate structure.

Amino Acids, Acidic↗

PubMed2006

Purification of polyglutamine proteins.

The misfolding and formation of fibrillar-like aggregates by polyglutamine proteins is believed to be a key factor in the development of the neurodegenerative polyglutamine diseases; however, relatively little is known about structural and conformational aspects of polyglutamine-induced misfolding and aggregation. This is largely attributable to the fact that polyglutamine proteins have proved difficult to purify in quantities suitable for biochemical and biophysical analyses, thus limiting the extent to which the proteins can be conformationally characterized. Recent advances, however, have seen the development of a number of protocols enabling the expression and purification of these proteins in more significant quantities. In this report, we describe a purification protocol for ataxin-3, which, in its polyglutamine-expanded form, causes Machado-Joseph disease. Purification of different length ataxin-3 variants, including one of pathological length, is facilitated by an N-terminal hexa-histidine tag, which enables binding to a nickel-chelated agarose resin. A key issue that arose during purification was the undesirable proteolysis of ataxin-3 by a trace contaminant protease. We solved this problem by the addition of a benzamidine-binding step during purification, which greatly reduced the level of proteases present. We found that the inclusion of this step had a significant positive impact on the quality of the purified protein product. We also inactivated trace amounts of proteases during experiments by the addition of specific protease inhibitors. Finally, we also describe initial structural and functional analyses that confirm the integrity of the purified protein.

Ataxin-3↗

PubMed1997

EBV-associated Kikuchi's histiocytic necrotizing lymphadenitis with cutaneous manifestations.

The clinical and pathologic findings of Kikuchi's histiocytic necrotizing lymphadenitis may mimic those of malignant lymphoma. We describe a 6-year-old boy with generalized lymphadenopathy, spiking fever, chills, myalgias, malaise, and erythematous, crusted papules. Although cutaneous manifestations have been noted in 16% to 40% of patients with histiocytic necrotizing lymphadenitis, only three publications described skin lesions. The skin lesions and affected lymph nodes revealed histiocytic aggregates, atypical lymphoid cells, karyorrhectic debris, and patchy necrosis. Spontaneous resolution occurred in 2 months. Results of serologic studies, Epstein-Barr virus (EBV) latent membrane protein immunoperoxidase staining, EBER-1 RNA in-situ hybridization, and EBV EBNA-1 DNA polymerase chain reaction implicate EBV as the causative agent.

Biopsy↗

PubMed2003

Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.

Cyclin-dependent kinase 5 (Cdk5) and its regulatory subunit p35 are integral players in the proper development of the mammalian central nervous system. Proteolytic cleavage of p35 generates p25, leading to aberrant Cdk5 activation. The accumulation of p25 is implicated in several neurodegenerative diseases. In primary neurons, p25 causes apoptosis and tau hyperphosphorylation. Current mouse models expressing p25, however, fail to rigorously recapitulate these phenotypes in vivo. Here, we generated inducible transgenic mouse lines overexpressing p25 in the postnatal forebrain. Induction of p25 preferentially directed Cdk5 to pathological substrates. These animals exhibited neuronal loss in the cortex and hippocampus, accompanied by forebrain atrophy, astrogliosis, and caspase-3 activation. Endogenous tau was hyperphosphorylated at many epitopes, aggregated tau accumulated, and neurofibrillary pathology developed progressively in these animals. Our cumulative findings provide compelling evidence that in vivo deregulation of Cdk5 by p25 plays a causative role in neurodegeneration and the development of neurofibrillary pathology.

Animals↗

PubMed2003

Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease.

Epidemiological studies of Alzheimer patients from a wide variety of ethnic and socioeconomic backgrounds have identified education and occupation as environmental factors that can affect the risk of developing disease. A model of environmental manipulation in rodents uses enriched housing to provide cognitive and social stimulation. Previous studies have established elevations in synaptic number and function in rodents housed under enriched conditions. Recent experiments in hippocampal cultures have demonstrated that synaptic activity can influence the processing of amyloid precursor protein (APP). Here we examined whether changes in synaptic activity brought about by enriched housing might also influence the deposition of amyloid plaques in vivo using a transgenic mouse model of Alzheimer disease (AD). Mice co-expressing mutant APP and presenilin 1 (PS1) were housed in either enriched or standard cages from 2 months of age and then killed for pathological evaluation several months later. We find that, as compared to littermates housed in standard cages, the enriched APP/PS1 transgenic mice develop a higher amyloid burden with commensurate increases in aggregated and total A beta. These results suggest that A beta deposition can be exacerbated by the neuronal changes associated with enrichment, and demonstrate a substantial, albeit paradoxical, environmental influence on the progression of pathology in a mouse model of AD.

Alzheimer Disease↗

PubMed1981

[Microcirculatory disorders in patients with cerebrovascular pathology].

The microvascular network of the labial mucosa and the nail bed, as well as the rheological properties of the blood were examined in 132 patients with various forms of cerebral circulation disorders. It was shown that the patients with the cerebrovascular pathology had organic changes of the capillaries. At the same time a hyperreactivity of the microvessels was observed. This hyperreactivity was more marked in patients with initial forms of the cerebrovascular disturbances. In the patients examined an increased permeability of te capillaries for protein and water was revealed: this increase was found to correlate with the disease gravity. Along with the vascular changes the patients also showed disturbances of the blood rheological properties. These disturbances manifested in an increased viscosity of the blood (especially at low shear speeds) and an increased aggregation of erythrocytes. It was also found that not only the erythrocyte aggregation, but also the strength of the aggregates formed were increased: this correlated well with the disease gravity.

Capillary Permeability↗

PubMed1997

Activation of human platelets by the membrane-expressed A1 domain of von Willebrand factor.

Platelet activation and microthrombus formation are invariable features of xenograft rejection and the vascular injury observed when porcine organs are transplanted into primates. This pathological process could be mediated, at least in part, by aberrant interactions of von Willebrand Factor (vWF) associated with the donor vasculature with host platelets. Unlike human vWF, native porcine vWF (pvWF) interacts with human GPIb independently of shear stress or nonphysiological stimuli, eg, ristocetin. We therefore contrasted the potential of isolated human and porcine vWF-A1-domains to interact with human platelets in vitro. Both human and porcine vWF-A1-domains expressed as glycosyl phosphatidylinositol-linked FLAG fusion proteins on COS-7 cells induced GPIb-dependent aggregation and intracellular Ca++ uptake of platelets, independent of both the remainder of the vWF protein and additional modifying factors. Porcine A1-domains were more potent than human homologues, and in addition ristocetin could boost platelet aggregation only with the human A1-domain. Putative conformational changes in the porcine A1-domain could result in the heightened, ristocetin-independent interactions observed with human platelets and may be of importance for xenograft survival.

Amino Acid Sequence↗

PubMed2000

Depression in alpha-synucleinopathies: prevalence, pathophysiology and treatment.

Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are increasingly recognized as alpha-synucleinopathies, i.e. neurodegenerative disorders that share a common subcellular pathology characterized by alpha-synuclein abnormal aggregation. In the present review we focus on depression in alpha-synucleinopathies, discussing epidemiological, pathophysiological and treatment aspects of this frequently disabling clinical feature which may occur in PD, DLB and MSA alike.

Animals↗

PubMed2006

Pin1 allows for differential Tau dephosphorylation in neuronal cells.

Neurofibrillary degeneration is likely to be related to abnormal Tau phosphorylation and aggregation. Among abnormal Tau phosphorylation sites, pThr231 is of particular interest since it is associated with early stages of Alzheimer's disease and is a binding site of Pin1, a peptidyl-prolyl cis/trans isomerase mainly involved in cell cycle regulation. In the present work, Pin1 level was found strongly increased during neuronal differentiation and tightly correlated with Tau dephosphorylation at Thr231. Likewise, we showed in cellular model that Pin1 allowed for specific Tau dephosphorylation at Thr231, whereas other phosphorylation sites were unchanged. Moreover, cells displaying Tau phosphorylation at Thr231 did not show any Pin1 nuclear depletion. Altogether, these data indicate that Pin1 has key function(s) in neuron and is at least involved in the regulation of Tau phosphorylation at relevant sites. Hence, Pin1 dysfunction, unlikely by nuclear depletion, may have critical consequences on Tau pathological aggregation and neuronal death.

Alzheimer Disease↗

PubMed1999

Pathogenic light chains and the B-cell repertoire.

Dysfunctional immunoglobulins (Igs) that are prone to aggregation are unavoidably generated by the diverse repertoire of B cells. Here, Fred Stevens and Yair Argon analyse the patterns of mutations that lead to pathological Igs, account for non-random mutations in human Ig sequences and suggest the exertion of selective forces, which contribute to determining and limiting the Ig repertoire.

B-Lymphocytes↗