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)

Hereditary cystatin C amyloid angiopathy (HCCAA), an autosomal dominant form of cerebral amyloid angiopathy (CAA) occurring primarily in Iceland, is characterized by a variant cystatin C amyloid deposition in the walls of cerebral parenchymal and leptomeningeal vessels. Cystatin C is also found to colocalize with amyloid beta/A4 protein in cerebral vessel walls of patients with Alzheimer's disease (AD), sporadic CAA, and hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D). The abundance of cystatin C deposition in cerebral blood vessel walls suggests that cellular elements of the vessel wall itself may play a role in its deposition. Microvascular changes in the brains of HCCAA patients were investigated by single- and double-label immunohistochemistry. We found that cystatin C amyloid immunoreactivity was present not only in cerebral cortical and leptomeningeal vessels, but also in white matter parenchymal vessels. Cystatin C deposition was more prominent in the media of parenchymal vessels and in the adventitia of leptomeningeal vessels. Smooth muscle (sm) cells were few or could not be identified within vessel walls showing extensive cystatin C deposition, suggesting progressive loss of these cells as cystatin C accumulates. However, in less severely affected vessels, cystatin C was present in cells that also had the phenotype of sm, suggesting that sm cells synthesize or process cystatin C. Cystatin C immunoreactivity was in addition, detected in some neuronal cell bodies throughout the cortex in patients with HCCAA and AD-related CAA. Our results indicate that cellular components of the vessel walls may play an important role in cystatin C deposition, as they do in beta/A4 deposition in AD-related CAA. Cystatin C deposition within the vascular media and adventitia, with associated vessel wall injury as manifested by sm cell loss, represents microvascular degeneration that leads to cerebral hemorrhage.
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PMID:Microvascular degeneration in hereditary cystatin C amyloid angiopathy of the brain. 906

To clarify the significance of the constituents of canine senile plaques (SPs) or cerebrovascular amyloid deposits, paraffin and cryostat sections of canine brains were examined by immunohistochemistry using antibodies against cathepsin B (CB), cathepsin D (CD), cystatin C (CC), alpha-1-antichymotrypsin (ACT), heat shock protein 70 (HSP70), ubiquitin (Ubq), and apolipoprotein E (Apo E). On the cryostat sections, all types of canine SPs and cerebrovascular amyloid deposits in both arterioles and capillaries were positive for Apo E. On paraffin sections, the Apo E immunoreactivity of diffuse plaques was weak and varied according to the method of fixation or pretreatment before immunostaining. Moreover, amyloid plaques were found to contain several elements that were positive for CC, ACT, CD, and Ubq, and a subset of vascular amyloid deposits around cortical capillaries showed significant immunoreactivity for CD, CC, and ACT. In addition, vascular amyloid deposits in the arterioles showed moderate CD immunoreactivity and were intensely Apo E positive. No significant labeling of canine Sps or vascular amyloid deposits was detected when the antibodies against CB and HSP 70 were applied to the cryostat and paraffin sections. These results indicated that, of the constituents examined, Apo E might be most closely related to canine beta-amyloidosis in the early stage of this brain disorder.
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PMID:Immunohistochemical study of constituents other than beta-protein in canine senile plaques and cerebral amyloid angiopathy. 908 60

To better understand the characteristics of amyloid deposition in the choroid plexus, we examined autopsied brain by routine histology, immunohistochemistry, and electron microscopy in three group of patients: primary systemic amyloidosis (n = 7), cerebral amyloid angiopathy (CAA, n = 6), and controls (n = 3). Three of the CAA patients had Alzheimer's disease. Congophilic, birefringent amyloid deposits of the choroid plexus were seen in six of the seven cases of systemic light chain amyloidosis. Immunohistochemistry revealed that the deposited amyloids had reactivity for immunoglobulin light chain and amyloid P component. Accumulation of macrophages labeled with monoclonal antibodies against CD 68 and major histocompatibility complex class II antigens were observed around the massive amyloid deposits. The presence of approximately 10 nm amyloid fibrils along the epithelial basement membrane as well as in the vascular walls was ascertained by electron microscopy. In CAA, Congo red-positive amyloid deposits were consistently present in meningeal blood vessels and were often found in senile plaques of the cerebral parenchyma; congophilic amyloid deposits were absent in the choroid plexus. Choroid plexus epithelial cells exhibited immunostaining for beta amyloid precursor protein (APP) with N-terminal- and C-terminal-specific antibodies; in particular, consistent staining was obtained for the latter antibody. Immunoreactivity for amyloid beta protein (A beta) with monoclonal antibodies (6E10, 4G8) was often found in choroid plexus epithelial cells. These findings suggest that amyloid deposition of the choroid plexus depends on the major component protein in amyloidosis, and that the choroid plexus may produce APP and A beta protein although A beta amyloidosis is not evident in the choroid plexus.
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PMID:Human choroid plexus is an uniquely involved area of the brain in amyloidosis: a histochemical, immunohistochemical and ultrastructural study. 917 87

To define the cellular processing of human cystatin C as well as to lay the groundwork for investigating its contribution to lcelandic Hereditary Cerebral Hemorrhage with Amyloidosis (HCHWA-I), we have characterized the trafficking, secretion, and extracellular fate of human cystatin C in transfected Chinese hamster ovary (CHO) cells. It is constitutively secreted with an intracellular half-life of 72 min. Gel filtration of cell lysates revealed the presence of three cystatin C immunoreactive species; an 11 kDa species corresponding to monomeric cystatin C, a 33 kDa complex that is most likely dimeric cystatin C and immunoreactive material, > or = 70 kDa, whose composition is unknown. Intracellular monomeric cystatin C is functionally active as a cysteine protease inhibitor, while the dimer is not. Medium from the transfected CHO cells contained only active monomeric cystatin C indicating that the cystatin C dimer, formed during intracellular trafficking, is converted to monomer at or before secretion. Cells in which exit from the endoplasmic reticulum (ER) was blocked with brefeldin A contained the 33 kDa species, indicating that cystatin C dimerization occurs in the ER. After removal of brefeldin A, there was a large increase in intracellular monomer suggesting that dimer dissociation occurs later in the secretion pathway, after exiting the ER but prior to release from the cell. Extracellular monomeric cystatin C was found to be internalized into lysosomes where it again dimerized, presumably as a consequence of the low pH of late endosome/lysosomes. As a dimer, cystatin C would be prevented from inhibiting the lysosomal cysteine proteases. These results reveal a novel mechanism, transient dimerization, by which cystatin C is inactivated during the early part of its trafficking through the secretory pathway and then reactivated prior to secretion. Similarly, its uptake by the cell also leads to its redimerization in the lysosomal pathway.
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PMID:Human cystatin C forms an inactive dimer during intracellular trafficking in transfected CHO cells. 936 56

Cerebral amyloid angiopathy (CAA) is a significant risk factor for hemorrhagic stroke in the elderly, and occurs as a sporadic disorder, as a frequent component of Alzheimer's disease, and in several rare, hereditary conditions. The most common type of amyloid found in the vasculature of the brain is beta-amyloid (A beta), the same peptide that occurs in senile plaques. A paucity of animal models has hindered the experimental analysis of CAA. Several transgenic mouse models of cerebral beta-amyloidosis have now been reported, but only one appears to develop significant cerebrovascular amyloid. However, well-characterized models of naturally occurring CAA, particularly aged dogs and non-human primates, have contributed unique insights into the biology of vascular amyloid in recent years. Some non-human primate species have a predilection for developing CAA; the squirrel monkey (Saimiri sciureus), for example, is particularly likely to manifest beta-amyloid deposition in the cerebral blood vessels with age, whereas the rhesus monkey (Macaca mulatta) develops more abundant parenchymal amyloid. These animals have been used to test in vivo beta-amyloid labeling strategies with monoclonal antibodies and radiolabeled A beta. Species-differences in the predominant site of A beta deposition also can be exploited to evaluate factors that direct amyloid selectively to a particular tissue compartment of the brain. For example, the cysteine protease inhibitor, cystatin C, in squirrel monkeys has an amino acid substitution that is similar to the mutant substitution found in some humans with a hereditary form of cystatin C amyloid angiopathy, possibly explaining the predisposition of squirrel monkeys to CAA. The existing animal models have shown considerable utility in deciphering the pathobiology of CAA, and in testing strategies that could be used to diagnose and treat this disorder in humans.
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PMID:Animal models of cerebral beta-amyloid angiopathy. 937 51

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

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

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

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

The beta-amyloid (A beta) peptide is present both in serum and in platelets, however it is unclear whether A beta plays a role in platelet function. We have now investigated the effects of soluble A beta on platelet function and have found that low levels (0.1-1 nM) of soluble A beta augment ADP-dependent platelet aggregation and translocation of focal adhesion kinase to the platelet cytoskeleton. Addition of A beta to gel-filtered platelets along with concentrations of adenosine diphosphate (ADP) producing submaximal aggregation responses increased the aggregation response by over 2-fold depending on the ADP:A beta ratios. The structure activity requirements for A beta activity showed intriguing constraints. Only full length A beta has significant activity. Truncated A beta peptides, such as A beta(1-16) or A beta(25-35), or reverse A beta(40-1) all show little or no activity. We also examined the activity of mutant A beta peptides, corresponding with the APP(692A-G) and APP(693E-Q) (at A beta21 and A beta22, respectively) which are found in familial Alzheimer's disease and hereditary cerebral hemorrhagic amyloidosis, Dutch type (HCHWA-D), and found that these peptides showed little or no activity. These results suggest that A beta interacts with platelets in a highly specific manner and may play a role in regulating platelet function.
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PMID:Beta-amyloid augments platelet aggregation: reduced activity of familial angiopathy-associated mutants. 985 75


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