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)

Cerebral amyloid beta-protein (Abeta) angiopathy (CAA) is a common pathological feature of Alzheimer's disease and several related disorders. In this condition, the accumulation offibrillar Abeta deposits is associated with degeneration of smooth muscle cells within the cerebral blood vessel wall. We have been using primary cultures of human cerebrovascular smooth muscle (HCSM) cells to investigate pathogenic mechanisms of Abeta in CAA. The specific assembly of Abeta fibrils on the surface of these cell types initiates several pathologic responses including increased expression and cell surface accumulation of the Abeta precursor protein (AbetaPP) and induction of apoptotic cell death. These pathologic responses are not observed with preparations of Abeta that are assembled into fibrils in solution, further underscoring the significance of the fibril assembly process on the cell surface. Since cell surface Abeta fibril assembly is the key initiator of the cerebrovascular cellular pathology that is observed in vitro, inhibition of this process remains an attractive therapeutic target for CAA. We have tested the efficacy of a variety of compounds that have been reported to inhibit Abeta fibril assembly in solution and block the neurotoxic properties of Abeta in vitro. The vast majority of these agents were ineffective in inhibiting the cell surface fibrillar assembly of Abeta and the subsequent pathologic responses in the cultured HCSM cells. This emphasizes the likely requirement of therapeutic compounds that are effective in disrupting cell surface-driven Abeta fibril assembly in the treatment of CAA.
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PMID:Disruption of pathologic amyloid beta-protein fibril assembly on the surface of cultured human cerebrovascular smooth muscle cells. 1167 86

Amyloid deposits characteristic of cerebral amyloid angiopathy lead to vessel rupture and intracerebral hemorrhage. Proteoglycans associate with the amyloid fibril deposits and are thought to play a role in the polymerization of amyloid proteins and the propagation of the deposition process. A series of low molecular weight anionic compounds was developed to mimic the glycosaminoglycan moieties of these proteoglycans. These compounds were tested in different in vitro systems to determine their anti-Abeta amyloid activity. Specific compounds were identified as being anti-fibrillogenic and protective against Abeta-induced cvtotoxicity. Such compounds also did not show intrinsic cellular toxicity could cross the blood-brain barrier (BBB) in vivo, and showed a good safety profile following chronic' exposure. Molecules showing an anti-amyloid profile combined with the ability to cross the BBB represent promising therapeutics for CAA.
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PMID:Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy. 1167 87

The term cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the walls of leptomeningeal and cortical arteries, arterioles and, although less frequently in capillaries and veins. It is commonly associated with Alzheimers disease, Down's syndrome and normal aging, as well as with a variety of familial conditions related to stroke and/or dementia: hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-I), various inherited disorders linked to Abeta mutants (including the Dutch variant of HCHWA), and the recently described chromosome 13 familial dementia in British and Danish kindreds. This review focuses on four different types of hereditary CAA, emphasizing the notion that CAA is not only related to stroke but also to neurodegeneration and dementia of the Alzheimer's type.
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PMID:Familial cerebral amyloid angiopathy related to stroke and dementia. 1167 88

The dense-cored plaques are considered the pathogenic type of amyloid deposition in Alzheimer's disease brains because of their predominant association with dystrophic neurites. Nevertheless, in > 90% of cases of Alzheimer's disease amyloid is also deposited in cerebral blood vessel walls (congophilic amyloid angiopathy; CAA) but its role in Alzheimer's disease pathogenesis remains enigmatic. Here, we report a family (family GB) in which early-onset Alzheimer's disease was caused by a novel presenilin 1 mutation (L282V). This was unusually severe CAA reminiscent of the Flemish amyloid precursor protein (A692G) mutation we reported previously, which causes Alzheimer's disease and/or cerebral haemorrhages. In family GB, however, the disease presented as typical progressive Alzheimer's disease in the absence of strokes or stroke-like episodes. Similarly, neuroimaging studies and neuropathological examination favoured a degenerative over a vascular dementia. Interestingly, an immunohistochemical study revealed that, similar to causing dense-cored amyloid plaques, CAA also appeared capable of instigating a strong local dystrophic and inflammatory reaction. This was suggested by the observed neuronal loss, the presence of tau- and ubiquitin-positive neurites, micro- and astrogliosis, and complement activation. Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration that occurs in Alzheimer's disease.
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PMID:Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation. 1170 93

The relationship between cerebral amyloid angiopathy and hemorrhage was investigated by an immunohistochemical study of biopsy cases to characterize the involvement of amyloid beta-protein, apolipoprotein E, and cystatin C in cerebral amyloid angiopathy associated with hemorrhage. The amyloid-laden vessels were examined in biopsy specimens from 41 surgical cases of sporadic cerebral amyloid angiopathy (36 cases with hemorrhage and 5 cases without hemorrhage), using immunohistochemical staining with antibodies against amyloid beta-protein, apolipoprotein E, cystatin C, and alpha-smooth muscle actin. The relationship between the occurrence, recurrence, and enlargement of the hemorrhage, and the semiquantitative estimation of the cerebrovascular amyloid-related protein deposition was analyzed using Fisher's exact test. Severe amyloid beta-protein (p < 0.013) and apolipoprotein E (p < 0.013) immunoreactivity were risk factors for the occurrence of the hemorrhage. Severe cystatin C immunoreactivity was a risk factor for the occurrence (p < 0.002) and enlargement (p < 0.014) of the hemorrhage, and tended to induce recurrent hemorrhage (p < 0.103). In addition, loss of the vascular smooth muscle was observed in the intensely amyloid-laden vascular walls that showed cystatin C-immunoreactivity. The present study indicates that intense amyloid beta-protein deposition with cystatin C deposition weakens the cerebrovascular walls, and that cystatin C deposition is a strong predictor of hemorrhage in cerebral amyloid angiopathy.
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PMID:Cerebral amyloid angiopathy associated with hemorrhage: immunohistochemical study of 41 biopsy cases. 1176 Mar 81

Cerebrovascular deposition of amyloid beta protein (A beta) is a characteristic lesion of Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). Besides A beta, several other proteins and proteoglycans accumulate in cerebral amyloid angiopathy (CAA). We have now analyzed the expression of the heparan sulfate proteoglycan (HSPG) subtypes agrin, perlecan, glypican-1, syndecans 1-3 and HS glycosaminoglycan (GAG) side chains in CAA in brains of patients with AD and HCHWA-D. Hereto, specific well-characterized antibodies directed against the core protein of these HSPGs and against the GAG side chains were used for immunostaining. Glypican-1 was abundantly expressed in CAA both in AD and HCHWA-D brains, whereas perlecan and syndecans-1 and -3 were absent in both. Colocalization of agrin with vascular A beta was clearly observed in CAA in HCHWA-D brains, but only in a minority of the AD cases. Conversely, syndecan-2 was frequently associated with vascular A beta in AD, but did not colocalize with vascular A beta deposits in HCHWA-D. The three different syndecans, agrin, glypican-1 and HS GAG, but not perlecan, were associated with the majority of senile plaques (SPs) in all brains. Our results suggest a role for agrin in the formation of SPs and of CAA in HCHWA-D, but not in the pathogenesis of CAA in AD. Both syndecan-2 and glypican, but not perlecan, may be involved in the formation of CAA. We conclude that specific HSPG species may be involved in the pathogenesis of CAA in both AD and HCHWA-D, and that the pathogenesis of CAA and SPs may differ with regard to the involvement of HSPG species.
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PMID:Heparan sulfate proteoglycan expression in cerebrovascular amyloid beta deposits in Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis (Dutch) brains. 1176 21

Cystatin-C, a cysteine protease inhibitor, and mannose binding lectin, an innate defense protein involved in microbial clearance, have both been hypothesized to mediate atherosclerotic plaque progression. Prospective data evaluating whether levels of these proteins are associated with incident cardiovascular disease are sparse. Employing a prospective, nested, case-control study design, baseline levels of cystatin-C and mannose binding protein were evaluated among 133 apparently healthy men who subsequently developed symptomatic peripheral arterial disease (cases) and among 133 age- and smoking-matched controls who remained free of reported vascular disease during 5 years of follow-up. Overall, median baseline levels of cystatin-C were virtually identical among case and control subjects (0.83 mg/l, p = 0.84), whereas median baseline levels of mannose binding protein among cases and controls were 2.32 mg/l and 2.20 mg/l respectively (p = 0.69). No evidence of association was found between either cystatin-C or mannose binding protein and the development of peripheral arterial disease in analyses evaluating for linear trends or for threshold effects (all p-values > 0.05). In contrast with prior retrospective and cross-sectional studies, no evidence was found that baseline levels of cystatin-C or mannose binding protein are associated with an increased risk of future arterial disease.
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PMID:Plasma levels of cystatin-C and mannose binding protein are not associated with risk of developing systemic atherosclerosis. 1178 68

Cerebral amyloid angiopathies are defined by the presence of amyloid substance in the walls of cerebral vessels. All amyloid substances have a particular physico-chemical structure, which imparts certain specific staining properties, but the biochemical composition of different amyloid types varies. Different forms of cerebral amyloid angiopathy have been identified, based on the biochemical nature of the protein deposited (e.g. beta-amyloid, cystatin C, transthyretin, gelsolin, amyloid protein Bri, prion protein). Some cerebral amyloid angiopathies are familial; these prompted genetic studies which in turn led to a better understanding of the genes coding for different amyloid proteins. As a group, cerebral amyloid angiopathies have certain neuropathological lesions in common. Infiltration by amyloid substance results in weakening of the small vessel walls and secondary complications responsible for changes such as microinfarcts and miliary haemorrhages in the cerebral cortex, lobar haemorrhages and/or leucoencephalopathy. These changes form the basis of the neurological complications: meningeal and cerebral haemorrhages, transient ischaemic episodes, vascular dementia. However each type of hereditary cerebral amyloid angiopathy has individual clinical and histopathological features reflecting the severity of arterial involvement, the extent of amyloid deposition within or outside the central nervous system, and the association with other neurodegenarative changes.
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PMID:[Hereditary cerebral amyloid angiopathies]. 1188 14

Cystatin C, a major extracellular cysteine proteinase inhibitor, is deposited as amyloid in brain haemorrhage patients with hereditary cystatin C amyloid angiopathy (HCCAA). A disease-causing mutation on the genetic level results in the substitution Leu68-->Gln (L68Q) in cystatin C, which causes protein instability. Besides carrying the L68Q substitution, cystatin C in amyloid deposits isolated from patients is N-terminally truncated by 10 amino acids. To elucidate the role of the N-terminal truncation for protein stability and aggregation properties, (delta1-10,L68Q)-cystatin C was produced in an Escherichia coli expression system and characterised. Unlike wild-type cystatin C, this variant rapidly dimerised under physiological conditions. Two unfolding intermediates of (delta1-10,L68Q)-cystatin C were identified, under the same pH and ionic strength conditions as required to form intermediates of full-length L68Q cystatin C. No evidence was found that the N-terminal truncation per se alters protein stability and leads to higher forms of aggregation. Monomeric as well as dimeric L68Q cystatin C incubated with neutrophil elastase was truncated as in HCCAA patients' amyloid. A protein variant with a thrombin cleavage site placed in front of residue Gly11 in L68Q cystatin C was constructed and used to confirm that the N-terminal segment is similarly accessible to proteinases in the monomeric and dimeric states of L68Q cystatin C. Thus, the N-terminal segment of L68Q cystatin C is exposed to proteolytic attack and does not seem to be involved in intramolecular contacts leading to dimerisation or higher-order aggregation. We conclude that the N-terminal truncation likely is an event secondary to amyloid formation, and of no relevance for the development of HCCAA.
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PMID:Physico-chemical properties of the N-terminally truncated L68Q cystatin C found in amyloid deposits of brain haemorrhage patients. 1193 68

It has been suggested that hyperhomocysteinemia observed in patients with occlusive vascular disease is caused by reduced renal function secondary to renovascular disease. We have therefore used serum cystatin C, a new sensitive marker for glomerular filtration, in 59 patients with acute coronary syndromes and high plasma homocysteine (tHcy) concentration to measure renal function. Samples were also obtained from 34 patients with low-normal plasma tHcy and 50 control subjects. The patients with low-normal plasma tHcy concentration showed decreased concentrations of serum cystatin C and serum creatinine and increased concentrations of blood folate and serum cobalamin compared to the controls and to the patients with high plasma tHcy. There was a large overlap in cystatin C concentrations between patients with high and low-normal plasma tHcy. None of the parameters investigated except plasma tHcy were significantly different in the group of patients with high plasma tHcy concentration compared to the control group. In order to further demonstrate the importance of renal impairment, a subgroup of the patients with high plasma tHcy was supplemented daily with folic acid 5 mg, pyridoxine 40 mg and cyancobalamin 1 mg for 3 months. Vitamin therapy reduced plasma tHcy from 18.3+/-4.6 pmol/l to 9.6+/-2.2 pmol/l (p<0.0001). However, vitamin treatment did not strengthen the correlation between cystatin C and plasma tHcy concentrations. These findings do not support the hypothesis that subtle renal dysfunction is an important cause of high plasma tHcy concentration in patients with acute coronary syndromes.
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PMID:Renal function exerts only a minor influence on high plasma homocysteine concentrations in patients with acute coronary syndromes. 1193 86


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