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)

This article describes 136 patients with hereditary cerebral haemorrhages; all patients belonged to families (originally) resident in Katwijk (The Netherlands). Cases of hereditary cerebral haemorrhage have also been reported in NW-Iceland, and in the Dutch coastal village of Scheveningen. Katwijk is a Dutch fishing-village, located 20 miles north of Scheveningen. These 136 cases were encompassed in three large pedigrees, and the disorder followed an autosomal dominant mode of inheritance. No connection between the pedigrees from Iceland, Scheveningen and Katwijk has as yet been established. In our series, sclerosis with amyloid deposits could be observed in roughly a quarter of the small arteries and arterioles in the cerebral cortex and the covering arachnoid. The pathological vessels were irregularly distributed in areas and clusters, possibly leading to superficial cerebral infarcts and, secondarily, to haemorrhages. Our findings are identical with those described in patients from Scheveningen, but different from the Icelandic group. In addition to some differences in the age at onset and in the distribution of the angiopathy, it has recently been demonstrated that the amyloid in our patients is constituted by a microprotein which shows a homology to the beta-protein in Alzheimer's disease and Down's syndrome, while the amyloid in Icelandic cases is formed by an aggregation of cystatin C (gamma trace). An unexpected finding in most of our patients is the accumulation of senile plaque-like lesions in the cerebral cortex. We did not observe Alzheimer's fibrillary tangles in any of our cases.
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PMID:Hereditary cerebral haemorrhage caused by cortical amyloid angiopathy. 321 24

Amyloid deposition is a prominent feature of a number of brain disorders, in which amyloid fibrils are found within blood vessel walls, the neuropil (neuritic plaques), neurons (neurofibrillary tangles). These include Alzheimer's disease (AD), AD changes associated with Down's syndrome, neurologically asymptomatic amyloidosis, Parkinson dementia of Guam, hereditary cerebral hemorrhage with amyloidosis of Icelandic origin (HCHWA-I), hereditary cerebral hemorrhage with amyloidosis of Dutch origin (HCHWA-D), and sporadic cerebral amyloid angiopathy (SCAA). Recently it was shown that the amyloid deposits in AD, Parkinson dementia of Guam, and HCHWA-D are formed by a similar 4-kd polypeptide called beta-protein. Because the nature of the amyloid deposits in other types of cerebral amyloidosis is not known, we have conducted immunocytochemical studies on brains from autopsy cases of AD, HCHWA-D, SCAA and neurologically asymptomatic elderly individuals. Brains from two subjects without neurologic involvement were used as controls. Sections from these specimens were incubated with rabbit polyclonal antibodies against 1) a synthetic peptide of 28 residues (anti-SP28), homologous to the NH2-terminal sequence of the beta-protein, 2) the main amyloid component of the HCHWA-I, a variant of cystatin C, and 3) purified fraction of neurofibrillary tangles. In all cases, anti-SP28 antibody specifically stained amyloid deposits in leptomeningeal and cortical vessels and neuritic plaques. These findings demonstrate that the amyloid deposits of SCAA and aged brains are composed of a protein antigenically similar to AD, HCHWA-D, and Parkinson dementia of Guam beta-protein, suggesting that all of these clinically and etiologically different morbid conditions are pathogenetically related. On this basis, they can be tentatively grouped as beta-protein deposition diseases. In addition, we found that HCHWA-D and SCAA vessels were mainly affected, while in AD parenchymal involvement predominates. These differences in the localization and extent of beta-protein deposits may account from the predominance of vascular complications in HCHWA-D and SCAA and of dementia in AD.
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PMID:Brain amyloid in normal aging and cerebral amyloid angiopathy is antigenically related to Alzheimer's disease beta-protein. 332 21

In hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D) beta/A4 amyloid deposition is found in meningocortical blood vessels and in diffuse plaques in the cerebral cortex. Diffuse plaques putatively represent early stages in the formation of senile plaques. Microglia are intimately associated with congophilic plaques in Alzheimer's disease (AD), but microglial involvement in diffuse plaque formation is controversial. Therefore, we studied the relationship between microglia and diffuse plaques in the cerebral cortex of four patients with HCHWA-D using a panel of macrophage/microglia markers (mAbs LCA, LeuM5, LeuM3, LN3, KP1, OKIa, CLB54, Mac1, Ki-M6, AMC30 and the lectin RCA-1). Eight AD patients, one demented Down's syndrome (DS) patient and four non-demented controls were included for comparison. In controls and HCHWA-D patients ramified or "resting" microglia formed a reticular array in cortical gray and subcortical white matter. Microglial cells in or near HCHWA-D diffuse plaques retained their normal regular spacing and ramified morphology. In AD/DS gray matter more microglial cells were stained than in controls and HCHWA-D patients. Intensely immunoreactive microglia with enlarged cell bodies and short, thick processes clustered in congophilic plaques. In contrast to the resting microglia, these "activated microglia" strongly expressed class II major histocompatibility complex antigen, HLA-DR, and were AMC30-immunoreactive. These findings support the view that microglia play a role in the formation of congophilic plaques but do not initiate diffuse plaque formation. Another finding in this study is the presence of strong monocyte/macrophage marker immunoreactivity in the wall of cortical congophilic blood vessels in HCHWA-D.
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PMID:Microglia in diffuse plaques in hereditary cerebral hemorrhage with amyloidosis (Dutch). An immunohistochemical study. 752 4

Recent molecular biological, biochemical and immunohistochemical studies have revealed various novel facts about beta-amyloidosis including its role in the pathogenesis of Alzheimer's disease (AD). Such discoveries include the finding that beta/A4-amyloid protein (beta-AP) is the major component of the amyloid found in senile plaques (SPs) and amyloid angiopathy, the elucidation of the molecular structures of beta-AP and beta-amyloid protein precursor (APP), the finding that point mutations of APP are involved in some cases of familial AD (FAD), the location of genes for FAD, APP and Down's syndrome on chromosome 21, and of other genes relating to AD on chromosomes 19, 14 and 6, and the successful development of Alzheimer-type neuropathology in transgenic mice overexpressing V717F APP, a mutation of APP. Furthermore, the involvement of various proteases and their inhibitors in metabolism of beta-AP have been suggested by: the presence of Kunitz class serine protease and metalloprotease inhibitor domains on some APP, the presence of various proteases and inhibitors in SPs and neurofibrillary tangles (NFTs), the involvement of various proteases in the secretory and endosome/lysosome pathways of APP processing, mutation of the APP gene in hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D), mutation of the cysteine proteinase inhibitor cystatin C gene in HCHWA-I (Iceland type), and abnormal increases of some proteases or the inhibitors in dystrophic neurites of SP, amyloid of SP, and NFTs. Judging from these reports, dysfunction or deregulation of proteolytic systems may play an important role in beta-amyloid formation. Recent studies of beta-amyloid and various proteases and inhibitors in disorders associated with beta-amyloid formation are reviewed including our 'overload hypothesis' as an underlying event in the dysfunction of proteolytic systems. This information should be helpful to identify targets in the development of drugs for the treatment of AD or other age-related disorders.
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PMID:The role of beta-amyloid in the development of Alzheimer's disease. 757 88

Brain amyloidosis with abundant beta/A4 protein deposition in plaques and cortical and meningeal vessels is found in Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). In contrast to AD, no neuritic pathology or classical congophilic plaques are found in HCHWA-D. Unlike most AD cases, the congophilic angiopathy in HCHWA-D is very severe. It is still unknown whether beta/A4 deposits in plaques and vessels have the same origin. In this study, we have used frozen cortical tissue of HCHWA-D and AD patients to investigate the beta/A4 amyloid protein and the amyloid precursor protein (APP) in different types of plaques and congophilic angiopathy. Immunohistochemical staining was conducted using antibodies against synthetic beta/A4 proteins and antibodies against APP including MAbP2-1, a monoclonal antibody against purified protease nexin-2, which is the secreted form of APP. In contrast to immunohistochemical studies on formalin-fixed, paraffin-embedded tissue, frozen tissue of HCHWA-D patients revealed a very high number of beta/A4 plaques resembling AD. All plaques were of the diffuse type. Double-staining with MabP2-1 and beta/A4 antisera revealed: 1) the presence of APP immunoreactivity in classical plaques and transitional forms; 2) the absence of APP immunoreactivity in diffuse plaques in HCHWA-D and AD; and 3) pronounced APP immunoreactivity in congophilic vessels in HCHWA-D in contrast to weak APP staining in congophilic vessels in AD. Together these findings suggest that: a) the presence of APP in plaques is related to neuritic changes; b) different processes occur in amyloid formation in plaques and vessels; and c) differences exist between the process of amyloid formation in HCHWA-D and AD.
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PMID:Distribution of beta/A4 protein and amyloid precursor protein in hereditary cerebral hemorrhage with amyloidosis-Dutch type and Alzheimer's disease. 768 95

Based on the recent discovery of co-localization of beta/A4 and cystatin C in cortical blood vessels of patients with cerebral hemorrhages due to sporadic amyloid angiopathy and patients with Alzheimer's disease we investigated the presence of these two proteins in the cortical blood vessels of patients suffering from hereditary cerebral hemorrhage with amyloidosis of the Dutch (n = 11) and the Icelandic (n = 2) type. The brains of three patients with sporadic cerebral amyloid angiopathy were also investigated. Blood vessels of the Dutch patients clearly showed immunostaining with beta/A4 as well as with cystatin C antibodies, whereas the blood vessels of Icelandic patients showed only staining with cystatin C. In one of the three sporadic amyloid angiopathy patients co-localization was shown as well. The co-localization of mutated beta/A4 with normal cystatin C in the Dutch patients suggests that cystatin C deposition occurs secondarily to beta/A4 deposition. This is probably also the case in sporadic amyloid angiopathy and Alzheimer's disease. Cystatin C deposition may play a role in the development of cerebral hemorrhages and leukoencephalopathy.
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PMID:Co-localization of beta/A4 and cystatin C in cortical blood vessels in Dutch, but not in Icelandic hereditary cerebral hemorrhage with amyloidosis. 808 35

Amyloid depositions mainly consist of proteins with a fibrillary structure. A large number of different proteins have amyloidogenic properties. Amyloids are now categorized on the basis of their chemical structure, but the clinical classification of localized and systemic amyloid is still useful. The proteins that can be found in cerebral amyloid angiopathy are cystatin C, beta/A4 and transthyretin. Cerebral amyloid angiopathy can remain symptom-free, but can also give a broad spectrum of clinical and radiological manifestations, including (vascular) dementia, cerebellar and cerebral hemorrhage, subarachnoid hemorrhage, and leukoencephalopathy. It is debated whether amyloid angiopathy plays a causative role in Alzheimer's disease, but it is strongly correlated with the presence of cerebral plaques. In this review, the clinical spectrum of cerebral amyloid angiopathy will be described, based on retrospective studies from the literature. Hereditary cerebral hemorrhage with amyloidosis (Dutch) will be presented as a 'prospective' model to study the clinical effects of amyloid angiopathy.
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PMID:Clinical aspects of cerebral amyloid angiopathy. 808 82

A 49-year-old man suffered from progressive dementia and seizures leading to death after 2 years. CT scans showed severe cortical-subcortical atrophy and hypodensity of the white matter. His father had died at about the same age with similar clinical signs. Two sisters and one brother were also affected. Neuropathological study revealed predominant involvement of the cerebral white matter with myelin loss, gliosis and type I lacunes. The small arteries and arterioles of the white matter and basal ganglia, and, to a lesser extent those of the subarachnoidal space, displayed fibrosis and replacement of the media by an eosinophilic, PAS positive, Congo Red negative, granular substance. Electron microscopy showed swollen myocytes surrounded by collagen, elastin and a compact electron-dense material. Immunofluorescence using antibodies against IgA, IgG, IgM, C1q and C3 stained the abnormal media weakly. In the cortex, there were diffuse senile plaques and neurofibrillary tangles. Immunohistochemistry demonstrated beta/A4 positive material in cortical senile plaques but not in arterial walls. Adventitial macrophages were, however, immunoreactive for gamma-trace. Systemic arterioles were normal. The vascular changes and leukoencephalopathy are comparable to those described in 'Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy' (CADASIL). Similar vascular changes were also observed in nonfamilial cases. An association with Alzheimer changes in the cortex has not been described previously. The relationship between both diseases and the role of each in the causation of the dementia is unclear.
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PMID:Autosomal dominant arteriopathic leuko-encephalopathy and Alzheimer's disease. 820 37

In cerebral amyloid angiopathy, the amyloid-beta (A beta) deposits lie primarily in the tunica media suggesting that smooth muscle cells play an important role in A beta deposition. To define this role, we conducted an immunocytochemical study of brain tissue from cases of Alzheimer disease with extensive cerebral amyloid angiopathy and cerebral hemorrhage. Antibodies specific to recombinant beta protein precursor (beta PP) and synthetic peptides homologous to various beta PP sequences from residue 18 to 689 of beta PP695 were used. Antibodies to actin, tropomyosin, alpha-actinin or desmin were used to label muscle cells. Antibodies to A beta sequences intensely recognized the extracellular amyloid deposit. Antibodies raised against beta PP sequences other than the A beta domain recognized smooth muscle cells. beta PP-immunoreactivity was reduced in regions of A beta deposits, since no muscle cells were recognized by cytoskeletal markers or observed ultrastructurally. In order to assess why A beta is deposited in the tunica media, we used biotin-labelled beta PP to determine if beta PP can be locally retained. We found beta PP bound to the tunica media of vessels but not other brain elements. These findings suggest A beta in blood vessels derives from degenerating beta PP-containing smooth muscle cells.
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PMID:Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease. 822 Oct 82

Expression of cystatin C and its mRNA in brain were investigated by use of immunohistochemical and polymerase chain-reaction techniques. High levels of cystatin C mRNA were detected in every region of rat brain examined, including the cerebral cortex, hippocampus, hypothalamus and cerebellum. Cystatin C-positive astrocytes were found by immunohistochemistry to be distributed throughout the brains of rat, monkey and human. Some neurons were also positive, but the staining was weak and variable. Intensely immunoreactive neurons were abundantly found in the cerebral cortex of some aged human cases and of all Alzheimer's disease patients. It is concluded that cystatin C is synthesized and expressed in the central nervous system, especially by astrocytes. Cystatin C might also be involved in the aging process of cortical neurons.
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PMID:Expression of cystatin C in rat, monkey and human brains. 831 75


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