Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), a genetic variant (E22Q) of amyloid beta (Abeta) accumulates predominantly in the small vessels of leptomeninges and cerebral cortex, leading to fatal strokes in the fifth or sixth decade of life. Abeta deposition in the neuropil occurs mainly in the form of preamyloid, Congo red negative deposits, while mature neuritic plaques and neurofibrillary tangles, hallmark lesions in Alzheimer's disease (AD), are characteristically absent. A recent hypothesis regarding the pathogenesis of AD states that Abeta extending to residues 42-43 (as opposed to shorter species) can seed amyloid formation and trigger the development of neuritic plaques followed by neuronal damage in AD. We characterized biochemically and immunohistochemically Abeta from three cases of HCHWA-D to determine its length in vascular and parenchymal deposits. Mass spectrometry of formic acid-soluble amyloid, purified by size-exclusion gel chromatography, showed that Abeta 1-40 and its carboxyl-terminal truncated derivatives were the predominant forms in leptomeningeal and cortical vessels. Abeta 1-42 was a minor component in these amyloid extracts. Immunohistochemistry with antibodies S40 and S42, specific for Abeta ending at Val-40 or Ala-42, respectively, were consistent with the biochemical data from vascular amyloid. In addition, parenchymal preamyloid lesions were specifically stained with S42 and were not labeled by S40, in agreement with the pattern reported for AD, Down's syndrome, and aged dogs. Our results suggest that in HCHWA-D the carboxyl-terminal Abeta heterogeneity is due to limited proteolysis in vivo. Moreover, they suggest that Abeta species ending at Ala-42 may not be critical for the seeding of amyloid formation and the development of AD-like neuritic changes.
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PMID:The length of amyloid-beta in hereditary cerebral hemorrhage with amyloidosis, Dutch type. Implications for the role of amyloid-beta 1-42 in Alzheimer's disease. 894 74

The systemic and cerebral accumulation of 123I-labelled serum amyloid P component (123I-SAP) was studied in patients with hereditary cerebral amyloid angiopathy-Dutch type (HCHWA-D) to determine the usefulness of 123I-SAP imaging in cerebral amyloidosis. Whole-body and SPET scintigraphic imaging was performed in two patients with HCHWA-D and four controls after the intraveous injection of 123I-SAP. Venous 123I-SAP clearance was also determined. Accumulation of the tracer was observed in the cerebral cortex of both patients, whereas no accumulation was seen in the controls. Blood clearance of radioactivity was similar in the patients and controls, suggesting that the amount of uptake of 123I-SAP in the cerebral amyloid deposits is relatively small. We believe this to be the first demonstration of cerebral amyloid deposits in vivo. Our findings indicate that 123I-SAP scintigraphy has possibilities for the diagnosis of patients with cerebral amyloid diseases, in addition to its use in patients with systemic amyloid deposition.
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PMID:Potential for imaging cerebral amyloid deposits using 123I-labelled serum amyloid P component and SPET. 897 63

Amyloid beta protein (A beta) deposition in the cerebral arterial and capillary walls is one of the major characteristics of brains from patients with Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). Vascular A beta deposition is accompanied by degeneration of smooth muscle cells and pericytes. In this study we found that A beta 1-40 carrying the "Dutch" mutation (HCHWA-D A beta 1-40) as well as wild-type A beta 1-42 induced degeneration of cultured human brain pericytes and human leptomeningeal smooth muscle cells, whereas wild-type A beta 1-40 and HCHWA-D A beta 1-42 were inactive. Cultured brain pericytes appeared to be much more vulnerable to A beta-induced degeneration than leptomeningeal smooth muscle cells, because in brain pericyte cultures cell viability already decreased after 2 days of exposure to HCHWA-D A beta 1-40, whereas in leptomeningeal smooth muscle cell cultures cell death was prominent only after 4-5 days. Moreover, leptomeningeal smooth muscle cell cultures were better able to recover than brain pericyte cultures after short-term treatment with HCHWA-D A beta 1-40. Degeneration of either cell type was preceded by an increased production of cellular amyloid precursor protein. Both cell death and amyloid precursor protein production could be inhibited by the amyloid-binding dye Congo red, suggesting that fibril assembly of A beta is crucial for initiating its destructive effects. These data imply an important role for A beta in inducing perivascular cell pathology as observed in the cerebral vasculature of patients with Alzheimer's disease or HCHWA-D.
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PMID:Rapid degeneration of cultured human brain pericytes by amyloid beta protein. 904 59

Arterial and arteriolar amyloid-beta (A beta) deposition in hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D) and Alzheimer disease (AD) cerebral amyloid angiopathy (CAA) were studied as to morphology, extent, and association with mononuclear phagocyte system (MPS) cells using A beta, a-smooth muscle actin, and monocyte/macrophage marker (HLA-DR, CD68, CD11c, CD45) immunohistochemistry. The HCHWA-D/AD arterial/arteriolar media showed compact A beta deposits, first appearing at the media/adventitia junction, and concomitant smooth muscle loss. Only HCHWA-D CAA featured (a) severe involvement of larger arteries and (b) arterioles showing a single or double ring of radial A beta surrounding compact A beta. Radial A beta appeared to develop at the media/adventitia junction. Monocyte/macrophage marker-positive foci/cells co-localized with HCHWA-D arterial A beta. Focal HLA-DR/CD11c positivity was observed at the media/adventitia junction of AD/HCHWA-D arteries in the absence of local A beta, but not in controls. Monocyte/macrophage marker positivity co-localizing with radial A beta appeared continuous with perivascular cells and microglia clustering perivascularly. These results suggest that (a) MPS cells are topographically associated with HCHWA-D arterial A beta and radial arteriolar A beta, and (b) HLA-DR/CD11c immunoreactivity may appear at the media/adventitia junction prior to A beta. The latter finding and the assumed formation of radial A beta at the media/adventitia junction may relate to involvement of the abluminal basement membrane in CAA pathogenesis. The role of MPS cells in this process remains to be established.
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PMID:Association of vascular amyloid beta and cells of the mononuclear phagocyte system in hereditary cerebral hemorrhage with amyloidosis (Dutch) and Alzheimer disease. 905 41

In a comparative study on the effects of predictive DNA testing for late onset disorders, pre-test psychological distress was assessed in people at risk for Huntington's disease (HD, n = 41), cerebral haemorrhage (HCHWA-D, n = 9), breast and ovarian cancer (HBOC, n = 24), and polyposis coli (FAP, n = 45). Partners, if available, also participated in the study. Distress was measured with the subscales Intrusion and Avoidance of the Impact of Event Scale. People at risk for the neurodegenerative disorders reported more avoidance than those at risk for the cancer syndromes. People at risk for FAP and partners of those at risk for HBOC reported less intrusion than the others at risk and the other partners. Subjects who were more distressed reported more experiences with the disease in close relatives, the disease having a great impact on their lives, having considerations against predictive testing, expecting that being identified as a gene carrier would have adverse effects, and expecting relief after being identified as a non-carrier. Test candidates who expected an increase of personal problems showed higher avoidance, whereas those who could better anticipate future life as a carrier had higher intrusion levels. Generally, subjects with high distress levels are of more concern to the healthcare professional than those with low distress levels. However, high distress may reflect worrying as a mental preparation for the test result, whereas low distress may indicate denial-avoidance behaviour and poor anticipation of the test outcome. In pre-test counselling sessions, this should be acknowledged and addressed.
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PMID:Psychological distress in applicants for predictive DNA testing for autosomal dominant, heritable, late onset disorders. The Rotterdam/Leiden Genetics Workgroup. 915 35

Cerebrovascular amyloid beta-protein (A beta) deposition is a key pathological feature of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). A beta(1-40) containing the E22Q HCHWA-D mutation, but not wild-type A beta(1-40), potently induces several pathologic responses in cultured human cerebrovascular smooth muscle cells, including cellular degeneration and a robust increase in the levels of cellular A beta precursor. In the present study, we show by several quantitative criteria, including thioflavin T fluorescence binding, circular dichroism spectroscopy, and transmission electron microscopic analysis, that at a concentration of 25 microM neither HCHWA-D A beta(1-40) nor wild-type A beta(1-40) appreciably assembles into beta-pleated sheet-containing fibrils in solution over a 6-day incubation period. In contrast, at the same concentrations, HCHWA-D A beta(1-40), but not wild-type A beta(1-40), selectively binds and assembles into abundant fibrils on the surfaces of cultured human cerebrovascular smooth muscle cells. The simultaneous addition of an equimolar concentration of the dye Congo red prevents the cell surface fibril assembly of HCHWA-D A beta(1-40). Moreover, Congo red effectively blocks the key pathologic responses induced by HCHWA-D A beta(1-40) in these cells. The present findings suggest that the surface of human cerebrovascular smooth muscle cells may selectively orchestrate the assembly of pathogenic A beta fibrils and that cell surface A beta fibril formation plays an important role in causing the pathologic responses in these cells.
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PMID:Pathologic amyloid beta-protein cell surface fibril assembly on cultured human cerebrovascular smooth muscle cells. 942 65

Hereditary cerebral haemorrhage with amyloidosis--Dutch type (HCHWA-D) is an autosomal dominant disorder, caused by a single base mutation in the amyloid beta precursor protein (beta PP) gene located on chromosome 21, resulting in recurrent haemorrhagic strokes and dementia. Though HCHWA-D is caused by a dominant mutation, the phenotypic expression varies widely, suggesting modulation of the phenotypic expression by additional factors. In this study we investigated the influence of sex, parental transmission and year of birth on mortality from HCHWA-D. Since the early sixties, clinical and genealogical data of patients with HCHWA-D have been collected. The standardized mortality rate (relative to the general population) was calculated to compare the mortality within the pedigrees with the mortality in the Dutch population. The influence of sex, parental transmission and year of birth on survival were studied using Cox's proportional hazard model. By December 1, 1995, a total of 187 cases were identified belonging to four large families. Mortality rate in affected individuals was fourfold increased compared with the Dutch population (relative mortality 4.0; 95% confidence interval 3.4-4.7) and higher in females than in males (relative mortality risk 8.0 and 2.6, respectively). Mortality rate was lower when HCHWA-D was maternally transmitted (mortality relative to paternal transmission 0.7; 95% confidence interval 0.5-1.0). Year of birth had no effect on the mortality of the affected individuals. Survival of HCHWA-D has not yet increased, in spite of higher standards of general medicine, i.e. the mortality rate did not decline over the years. Female sex was a major factor increasing mortality rate in HCHWA-D. Paternal transmission had a just significant effect on mortality rate in HCHWA-D. The possible mechanisms behind these phenomena remain unexplained by this clinical study.
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PMID:Mortality from hereditary cerebral haemorrhage with amyloidosis--Dutch type. The impact of sex, parental transmission and year of birth. 944 79

To investigate the relationship between cerebral amyloid angiopathy (CAA) and cystatin C, we studied five CAA patients on whose cerebral blood vessels colocalization of cystatin C and beta-protein was recognized immunohistochemically. One patient was suspected as familial CAA and the other patients were sporadic cases. Two patients had low concentration of cystatin C in their cerebrospinal fluid (CSF) as we have previously reported in CAA patients. Enzyme-linked immunosorbent assay (ELISA) revealed that cystatin C and beta-protein have been included at the ratio of about 1:100 in the crude amyloid fibrils of one patient. Using a monoclonal antibody (MAb) against cystatin C, we performed affinity chromatography and immunoblotting on her amyloid fibril fraction. Eluate showed a band with a mol wt of 14,000 and the N-terminal 14 amino acid residues of 14-kDa protein were identical with that of cystatin C. This molecular weight is not identical to that of the truncated form of cystatin C deposited in hereditary cerebral hemorrhage with amyloidosis in Iceland (HCHWA-I), but that of normal cystatin C. DNA sequence analysis of five patients showed no point mutations in the cystatin C gene. Cystatin C and beta-protein colocalization, which was recognized in amyloid lesions of CAA, suggests that cystatin C deposition may be related to beta-protein deposition. We hypothesize that cystatin C deposition in sporadic cerebral amyloid angiopathy with cystatin C deposition (SCCAA) involves a different mechanism from that in HCHWA-I, which may be related to low CSF concentration of cystatin C without amino acid substitutions.
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PMID:No mutations in cystatin C gene in cerebral amyloid angiopathy with cystatin C deposition. 949 77

Various secondary microvascular degenerative and inflammatory alterations may complicate cerebral amyloid angiopathy (CAA) and contribute to the morbidity of CAA-associated stroke. We have investigated the severity of CAA-associated microangiopathy in a genetically determined Dutch form of CAA (HCHWA-D) that has major similarities to the type of CAA that more commonly occurs with aging or Alzheimer's disease (AD). The presence and extent of the following vascular abnormalities was assessed: (1) hyalinization/fibrosis, (2) microaneurysm formation, (3) chronic (especially lymphocytic) inflammation, (4) perivascular multinucleated giant cells/granulomatous angiitis, (5) macrophages/histiocytes within the vessel wall, (6) vessel wall calcification, (7) fibrinoid necrosis, and (8) mural or occlusive thrombi. (Of these, calcification of CAA-affected vessel walls has, to our knowledge, been described in only a single patient with CAA-associated cerebral hemorrhage.) Some of the changes, such as histiocytes in blood vessel walls and the relationship of vascular hyalinosis to amyloid beta/A4 protein deposition, were highlighted by immunohistochemistry. By assessing the numbers of sections in which the changes were present for each case, a 'score' reflective of CAA-associated angiopathy could be obtained. This 'score' was reproducible among several observers. We suggest that it might also be applicable to quantifying severe CAA and related microvascular degenerative changes in patients with AD. beta/A4 immunoreactivity was often sparse and adventitial (or almost absent) in severely hyalinized arterioles and microaneurysms. However, macrophages were prominent in the walls of such vessels and may play a role in the pathogenesis and progression of CAA-related microvasculopathy.
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PMID:Secondary microvascular degeneration in amyloid angiopathy of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D). 954 88

A cystatin C variant with L68Q substitution and a truncation of 10 NH2-terminal residues is the major constituent of the amyloid deposited in the cerebral vasculature of patients with the Icelandic form of hereditary cerebral hemorrhage with amyloidosis (HCHWA-I). Variant and wild type cystatin C production, processing, secretion, and clearance were studied in human cell lines stably overexpressing the cystatin C genes. Immunoblot and mass spectrometry analyses demonstrated monomeric cystatin C in cell homogenates and culture media. While cystatin C formed concentration-dependent dimers, the HCHWA-I variant dimerized at lower concentrations than the wild type protein. Amino-terminal sequence analysis revealed that the variant and normal proteins produced and secreted are the full-length cystatin C. Pulse-chase experiments demonstrated similar levels of normal and variant cystatin C production and secretion. However, the secreted variant cystatin C exhibited an increased susceptibility to a serine protease in conditioned media and in human cerebrospinal fluid, explaining its depletion from the cerebrospinal fluid of HCHWA-I patients. Thus, the amino acid substitution may induce unstable cystatin C with intact inhibitory activity and predisposition to self-aggregation and amyloid fibril formation.
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PMID:Instability of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type. 956 5


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