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)

Clinical, radiological, and immunohistochemical findings in brain biopsy specimens from six patients with cerebral amyloid angiopathy-associated intracerebral hemorrhage were reviewed. Acute clinical presentations included headache, nausea and vomiting, loss of consciousness, and focal neurological deficits such as hemiplegia and blindness. Transient ischemic attacks experienced by one patient and referable to one hemisphere did not indicate impending hemorrhage in that region. Computed tomographic scans revealed acute, irregular, superficial, lobar hemorrhage with occasional ring enhancement. Immunohistochemical studies were performed on biopsy specimens using primary antibodies against portions of the Alzheimer A4 (beta-) peptide or gamma-trace peptide (the vascular amyloid protein in patients with hereditary cerebral hemorrhage with amyloidosis-Icelandic type). In all patients, anti-A4 and anti-gamma-trace labeled cerebral microvessels. Immunoreactive senile plaques were few compared with the numbers of stained microvessels. Reactive astrocytes in some patients were labeled by both antiserum samples, suggesting uptake or production of these proteins by the astrocytes. This study demonstrates the heterogeneous clinical and radiological features of cerebral amyloid angiopathy-related brain hemorrhage and the value of anti-A4 and anti-gamma-trace immunohistochemical study of biopsy material from patients with suspected cerebral amyloid angiopathy-related intraparenchymal bleeding.
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PMID:Cerebral hemorrhage with biopsy-proved amyloid angiopathy. 172 64

To clarify the pathogenesis of cerebrovascular amyloid deposits, histological and immunocytochemical studies were performed on the central nervous system (CNS) in ten cases with type I familial amyloid polyneuropathy (FAP). They commonly suffered from peripheral somatic and autonomic nerve disorders without any CNS dysfunctions. However, all cases showed CNS amyloid deposits, mainly on the leptomeningeal vessels and pia-arachnoid membranes, with arteries and arterioles in the subarachnoidal space being the predominant site of cerebral amyloid accumulation. Using immunocytochemical staining methods with antibodies to amyloid beta-protein, human cystatin C and transthyretin (prealbumin), all of these amyloid deposits were specifically immunolabeled by the anti-human transthyretin antibody. However, there was no transthyretin-related amyloid deposits in the brain parenchyma. It is concluded that CNS transthyretin-immunoreactive amyloid deposition with cerebral amyloid angiopathy (CAA) is a common pathological finding in this disease. Moreover, the patients with type I FAP are known to have an amyloid protein precursor (a variant of transthyretin) in serum. This transthyretin type of CAA, therefore, seems to be an example of cerebrovascular amyloid deposits derived from a serum precursor.
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PMID:Transthyretin-type cerebral amyloid angiopathy in type I familial amyloid polyneuropathy. 185 83

Polyclonal antibodies to synthetic peptides homologous to amino acid residues 45-62, 597-624, and 676-695 of the predicted sequence of Alzheimer's amyloid precursor protein (APP) were used to investigate the site of origin of APP, and the relationship between APP and amyloid protein in Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D). Cortical sections as well as homogenates of isolated leptomeningeal and cortical microvessels from three patients with AD, two patients with HCHWA-D, and two nondemented controls were probed. In vessel extracts of both groups of patients and the controls, APP was detected as a set of proteins with electrophoretic mobility of 105 to 135 kilodaltons. In cortical sections of all subjects, APP immunoreactivity was found in leptomeningeal and cortical vessel walls. In patients with AD and HCHWA-D, APP and amyloid fibrils coexisted in the same vessels. Moreover, APP immunoreactivity was found in association with 50% of senile plaques in AD brains, but was not evidenced in parenchymal amyloid deposits in patients with HCHWA-D. These data suggest that the vascular system is a source of APP and that the processing of APP into insoluble fibrils in AD and HCHWA-D may take place in situ.
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PMID:Coexistence of Alzheimer's amyloid precursor protein and amyloid protein in cerebral vessel walls. 211 97

Amyloid fibrils deposited in cerebral vessel walls in Dutch patients with hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) are formed by polymerization of a 39-residue peptide similar to the beta-protein of Alzheimer's disease, Down syndrome, sporadic cerebral amyloid angiopathy and normal aging. Sequence analysis of genomic DNA in HCHWA-D patients demonstrated a point mutation, cytosine for guanine at position 1852 of the precursor beta-protein gene, which causes a single amino acid substitution (glutamine for glutamic acid) corresponding to position 22 of the amyloid protein. The normal allele was also present in these patients. To examine the expression of normal and variant beta-protein alleles in HCHWA-D we analyzed all the tryptic peptides obtained from several amyloid fractions from leptomeningeal vascular walls. Amino acid sequence of two peptides (T3a and T3b) with identical amino acid composition revealed that T3a had glutamine and T3b had glutamic acid at position 22. Thus both the normal and variant Alzheimer's beta-protein alleles are expressed in vascular amyloid in HCHWA-D and may be detected by tryptic peptide mapping. Moreover, we have developed a diagnostic assay for high risk populations and prenatal evaluation that is based on the existence of the mutation.
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PMID:Expression of a normal and variant Alzheimer's beta-protein gene in amyloid of hereditary cerebral hemorrhage, Dutch type: DNA and protein diagnostic assays. 219 78

Using immunohistochemical staining methods with antibodies to amyloid beta protein and human cystatin C, we examined cerebrovascular amyloid protein in the brains from 46 cases with cerebral amyloid angiopathy (seven with Alzheimer's disease, one with Down's syndrome, 18 with intracranial hemorrhage, 10 with cerebral infarction, and 10 elderly patients without any neurologic disorder). All cerebrovascular amyloid deposits in these 46 cases were consistently immunoreactive to anti-beta protein antibody. However, in nine cases some vascular walls with strong beta protein immunoreactivity also reacted less intensely with the anti-cystatin C antiserum. Of these nine cases, seven showed relatively heavy cerebrovascular amyloid deposition, and all seven had suffered a fatal subcortical hemorrhage presumably caused by cerebral amyloid angiopathy. Previous limited studies have suggested that the amyloid protein seen in elderly individuals with cerebral amyloid angiopathy is composed of beta protein. However, subcortical hemorrhage rarely occurs in such individuals. Our study shows that aged patients with different brain disorders commonly suffer from beta protein-type cerebral amyloid angiopathy, and we also suggest that the severity of beta protein-type cerebrovascular amyloid deposition is a fundamental factor in cerebral amyloid angiopathy-induced brain hemorrhage in the elderly. The nature of the cystatin C-immunoreactive substance in some of these vascular lesions is uncertain, but it might conceivably play an additional important role in the pathogenesis of brain hemorrhage in these cases.
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PMID:Immunohistochemical characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to beta protein and cystatin C. 221 20

Hereditary Cerebral Hemorrhage With Amyloidosis is an autosomal dominant form of amyloidosis restricted to the cerebral vasculature. We have previously demonstrated that the amyloid protein subunit is similar to Cystatin C (or gamma-trace), an inhibitor of lysosomal cysteine proteinases, and homologous to kininogens. High pressure liquid chromatography tryptic fingerprint analysis was developed to distinguish Cystatin C from the amyloid protein. Moreover, we isolated and sequenced tryptic peptides in which the differences were detected. The data prove that the amyloid protein is 10 residues shorter than Cystatin C and has one amino acid substitution at residue 58.
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PMID:Hereditary cerebral amyloid angiopathy: the amyloid fibrils contain a protein which is a variant of cystatin C, an inhibitor of lysosomal cysteine proteases. 370 86

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

Plaque-like lesions and amyloid angiopathy were investigated in the frontal cerebral cortex of four patients with hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D), using immunohistochemical [antibodies to beta amyloid protein (A beta), beta protein precursor (beta PP), synaptophysin, ubiquitin (UBQ), cathepsin D, paired helical filaments (PHF) and glial fibrillary acidic protein (GFAP)], enzymehistochemical (acid phosphatase) and silver [methenamine silver (MS) and Palmgren] staining methods. Whereas A beta- and MS-positive diffuse plaques were found in all patients, only the three older patients showed neuritic or congophilic plaques, which were acid phosphatase and cathepsin D positive and contained beta PP-, synaptophysin- and UBQ-positive, but PHF-negative neurites. These plaques were surrounded by reactive astrocytes. Similar immuno- and enzymereactivity was found around congophilic blood vessels. Thus, apart from neuronal degeneration in a subset of plaque-like lesions and around blood vessels, this study shows an age-related morphology of the plaques in HCHWA-D, corresponding to that in Down's syndrome (DS), with the difference that neurofibrillary (NF) pathology is absent in HCHWA-D in contrast to DS. HCHWA-D may be considered as a model for congophilic plaque formation not associated with NF pathology.
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PMID:Hereditary cerebral hemorrhage with amyloidosis (Dutch): a model for congophilic plaque formation without neurofibrillary pathology. 783 31

Hereditary Cystatin-C Amyloidosis (HCCA) is a genetic disorder in Icelandic families in which a defective cystatin-C amyloid protein is deposited in the walls of small and middle sized arteries. Cerebral vessels are most affected, resulting in recurrent cerebral hemorrhages and infarctions, usually with onset of clinical symptoms in the twenties or thirties and a rapidly deteriorating clinical course. The disease can be diagnosed by a skin biopsy in symptomatic patients. We report two patients (father and daughter) who did not have a known family history of the disorder and presented late in life with a progressive dementia, associated with cerebral hemorrhages in the younger patient. Cerebral MRI and CT scans of this patient showed extensive leukoencephalopathic changes. Brain tissue samples from both patients showed immunohistochemical reaction to cystatin-C in small and medium-sized cerebral arteries and extensive cortical and white matter microinfarctions. The amyloid changes were less severe in the older patient and a colocation of beta-amyloid protein and cystatin-C was observed in addition to neurofibrillary tangles and senile plaques. Subcortical and cortical infarctions were also observed. HCCA may present late in life with progressive dementia as the only clinical manifestation, reflecting a multi-infarct syndrome secondary to the amyloidosis. A coexpression of cystatin-C and beta protein may occur as in other cerebral amyloid disorders, probably as age-specific changes.
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PMID:Progressive dementia and leucoencephalopathy as the initial presentation of late onset hereditary cystatin-C amyloidosis. Clinicopathological presentation of two cases. 886 34

Mutations at codons 717 and 670/671 in the amyloid precursor protein (APP) are rare genetic causes of familial Alzheimer's disease (AD). A mutation at codon 693 of APP has also been described as the genetic defect in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). We have reported a APP692Ala-->Gly (Flemish) mutation as a cause of intracerebral hemorrhage and presenile dementia diagnosed as probable AD in a Dutch family. We now describe the post-mortem examination of two demented patients with the APP692 mutation. The neuropathological findings support the diagnosis of AD. Leptomeningial and parenchymal vessels showed extensive deposition of Abeta amyloid protein. Numerous senile plaques consisted of large Abeta amyloid cores, often measuring more than 30 microm in diameter and were surrounded by a fine meshwork of dystrophic neurites. In addition, there were a large number of paired helical filaments in pyramidal neurons and dystrophic neurites. Our findings show that the APP692 mutation leads to morphological abnormalities that are similar to AD, but the morphology of senile plaques is clearly distinct from that described in sporadic and chromosome 14-linked AD patients, in patients with APP717 mutations causing familial, presenile AD and in patients with the APP693 mutation causing HCHWA-D.
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PMID:Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly mutation. 975 58


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