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PubMed1997

Immunocytochemical study of cathepsin L and rat salivary cystatin-3 in rat osteoclasts treated with E-64 in vivo.

The localization of cathepsin L and rat salivary cystatin-3 (RSC-3) in rat osteoclasts (rat femoral and alveolar bones) treated with or without E-64 (control) was examined immunocytochemically. In osteoclasts pretreated with E-64, immunoreactivity for cathepsin L was very weak extracellularly compared to that in the control osteoclasts. However, it was strong intracellularly. The localization of RSC-3 was unclear in the control osteoclasts, while in E-64 treated osteoclasts, both the clear zone and ruffled border areas showed a very strong immunoreaction. At the electron-microscopic level, in normal osteoclasts, numerous immunoreaction products for cathepsin L were found extracellularly in the bone matrix under the ruffled border, while few intracellular products were observed. In contrast, in the E-64-treated osteoclasts, only a few immunoreaction products were found extracellularly, while intracellularly cathepsin L was found in numerous endosome-lysosomal vacuoles. In the immunoreaction for RSC-3, the cytoplasm of the ruffled border was positive, and the tips of the RSC-3-positive ruffled border appeared to enter deeply into the bone matrix. Intracellularly, the granular reaction products of RSC-3 were found in the vacuoles (probably autophagolysosomes). Thus, in E-64-treated osteoclasts, inhibition of the extracellular release of cathepsin L was demonstrated. In addition, intralysosomal accumulation of RSC-3 and deep penetration of the RSC-3-positive ruffled border into the bone matrix were found. These findings suggest that RSC-3 is associated with the inhibition of cathepsin L in both the lysosomes (in the osteoclasts) and bone matrix.

Animals↗
PubMed2003

Cystatin-B is expressed by neural stem cells and by differentiated neurons and astrocytes.

Mutation in the gene encoding cystatin-B (CSTB) has been shown to cause progressive myoclonus epilepsy. Mice with a gene deletion of CSTB exhibit increased apoptosis of specific neurons but the physiological role of CSTB in brain cells is not fully understood. In the present study, we have examined the expression of CSTB in neural stem cells (NSC) and in differentiating mature brain cells. The results show that CSTB is present in embryonic and adult NSC and in the neuroepithelium. CSTB was expressed by both neurons and glial cells differentiated from NSC and in hippocampal cultures. CSTB localized mainly to the nucleus in NSC and in neurons, whilst in astrocytes CSTB was also in the cytoplasm. Double labeling showed that CSTB was present in the lysosomes in glial cells. The results demonstrate a nuclear expression of CSTB in NSC and in neurons, suggesting novel function for this molecule.

Animals↗
PubMed2000

Clinical value of cystatin C determination.

It has been reported that cystatin C (cys-C) is elevated in patients with malignant disease. In order to investigate whether this phenomenon is linked to or independent of renal function, and at the same time examine the role of this marker in other pathological situations, cys-C concentrations were compared with 24-h creatinine clearance values in three groups of patients; the first group were undergoing treatment for malignant disease, the second group were renal transplant patients and the third randomly taken from patients for whom a routine creatinine clearance had been requested. Several patients with malignant disease had high cys-C levels without any correspondence to creatinine clearance values. Additionally, although cys-C shows a high sensitivity for detecting impaired glomerular function in renal transplant patients, the specificity was very low, with little discrimination being observed between patients with normal and pathological creatinine clearance levels. In other patients both the sensitivity and specificity of cys-C could be shown to be very good. Thus although cys-C can generally be recommended as a marker of the glomerular filtration rate, there are some patients for whom the clinical relevance is unclear.

Biomarkers↗
PubMed2002

Measurement of cystatin-C and creatinine in urine.

BACKGROUND: The concentration of serum cystatin-C (Cys-C) is highly correlated with creatinine (Cr), and is mainly determined by glomerular filtration; thus, Cys-C may be an index of the glomerular filtration rate (GFR). However, the kinetics of urinary Cys-C and Cr excretions are unclear. Thus, we investigated the kinetics of urinary Cys-C and Cr excretions, and examined whether the urinary Cys-C concentration can be used as a marker of renal function. METHODS: The urinary excretion of Cys-C and Cr was evaluated in 1670 healthy subjects and 217 patients with proteinuria. We also investigated the urinary Cys-C concentration in 52 patients with chronic renal failure. RESULTS: There was a good correlation between the urinary concentrations of Cys-C and Cr in the healthy group. This relation was also observed in patients showing persistent proteinuria without tubular cell damage. The mean urinary Cr concentration increased with age, and it was affected by the muscle mass. In contrast, the urinary Cys-C concentration was not affected by the muscle mass, and the concentration remained constant for all ages. We further found that the ratio of Cys-C to Cr (CCR) is a good index of the state of Cys-C reabsorption in the proximal tubules. CONCLUSIONS: The urinary CCR can be a marker of renal tubular dysfunction. In addition, when CCR was in the normal range, the urinary Cys-C concentration accurately reflected the glomerular filtration function.

Adolescent↗
PubMed2003

Serum cystatin C in the aged: relationships with health status.

BACKGROUND: Serum cystatin C (Cys C) is claimed to be superior to serum creatinine (Cr) in estimating glomerular filtration rate, but its utility in assessing renal function in the polymorbid elderly needs to be evaluated. METHODS: In a cross-sectional, community-based survey performed in Lieto in southwestern Finland, Cys C, Cr, and urinary albumin-creatinine ratio (ACR) were measured in 1,260 subjects aged 64 to 100 years. Associations of demographic characteristics and health status factors with levels of Cys C, Cr, and ACR were assessed by means of linear models. RESULTS: In men, hypertension, coronary heart disease, urinary infection, rheumatoid arthritis, glucocorticoid treatment, older age, and lower functional status were found to be significant predictors of higher Cys C values, whereas hypertension, coronary heart disease, urinary infection, older age, and increasing body mass index (BMI) significantly predicted higher Cr values. Among women, corresponding factors were hypertension, glucocorticoid treatment, age, functional status, and BMI for Cys C and hypertension, BMI, and age for Cr. Diabetes was significantly associated only with ACR. These factors explained 35% of variation in Cys C values in men and 34.5% in women versus only 14.8% and 11.3% for Cr, respectively. CONCLUSION: Glucocorticoid treatment was recognized as an independent Cys C-increasing factor, presumably nonglomerular. In comparison with Cys C, a considerably greater proportion of total variation in Cr values seems to be explained by extrarenal factors.

Aged↗
PubMed2000

Characterization of the cystatin B gene promoter harboring the dodecamer repeat expanded in progressive myoclonus epilepsy, EPM1.

Mutations in the gene encoding cystatin B (CSTB) are responsible for the primary defect in progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1). A novel and unique type of disease-causing mutation, an unstable dodecamer repeat expansion, accounts for the majority of EPM1 patients world-wide. This minisatellite repeat expansion, located in the putative promoter of CSTB 175 bp upstream from the translation initiation codon, appears to downregulate CSTB gene expression in vivo. We report here the characterization of the CSTB promoter using different promoter-luciferase gene constructs. Transient transfections of cultured mammalian cells suggest that the region from -670 to -1 bp from the translation initiation codon functions as the CSTB promoter. Active binding to five Sp1 and four AP1 sites as well as weak binding to an androgen response element (ARE) half site was demonstrated by electrophoretic mobility shift assays. The effect of the minisatellite expansion on the promoter activity was evaluated by comparing the activity of constructs containing wild-type and expanded alleles. An increase in the number of dodecamer units from three to 19 repeats lowered transcription in vitro by 10-fold. Northern analysis of lymphoblastoid RNA from individuals with 'premutation' length dodecamer repeat (12-17 copies) expansions showed decreased levels of CSTB mRNA expression. These data indicate that expansion of the dodecamer repeat located in the proximal promoter of CSTB severely disrupts the function of the promoter and thereby reduces transcription of CSTB.

Animals↗
PubMed2003

Evolution of the cystatin B gene: implications for the origin of its variable dodecamer tandem repeat in humans.

The human cystatin B gene contains a variable number of 12-bp tandem repeats in its promoter region, of which the common alleles contain two or three copies and unusual expansion causes progressive myoclonus epilepsy of the Unverricht-Lundborg type. We undertook a comprehensive analysis of the genomic sequence to address the evolutionary events of this variable repeat. By examination of a contiguous genome sequence spanning 5.0 kb and linkage analysis of detected polymorphic changes, we identified six major intragenic haplotypes in unrelated Japanese subjects. The number of normal repeats was closely correlated with these alleles, indicating that changes in the array should be comparatively rare events during human evolution. To examine the origin of the repeat array further, we also analyzed five primate genomes. Repetitive polymorphism was unlikely in hominoids, and the array originated with the dodecamer itself in the course of primate evolution. The variability conceivably developed after the separation to humans.

Cystatin B↗
PubMed2003

Alzheimer disease-associated cystatin C variant undergoes impaired secretion.

CST3 is the coding gene for cystatin C (CysC). CST3 B/B homozygosity is associated with an increased risk of developing Alzheimer disease. We performed CysC analysis on human primary skin fibroblasts obtained from donors carrying A/A, A/B, and B/B CST3. Pulse-chase experiments demonstrated that the release of the B variant of CysC has a different temporal pattern compared to that of the A one. Fibroblasts B/B homozygous displayed a reduced secretion of CysC due to a less efficient cleavage of the signal peptide, as suggested by high-resolution Western blot analysis and by in vitro assay. In the brain, the reduced level of CysC may represent the molecular factor responsible for the increased risk of Alzheimer disease.

Aged↗
PubMedDate not supplied

Evaluation of cystatin C and beta-2 microglobulin as markers of renal function in patients with type 2 diabetes mellitus.

BACKGROUND: Despite recent studies showing that serum cystatin C (CC) is a better marker for GFR than the ubiquitously used serum creatinine, its clinical utility remains under evaluation. METHODS: To evaluate their usefulness in patients with type 2 diabetes mellitus (DM), serum concentrations of CC, beta-2 microglobulin (B2M) and creatinine were measured in 105 (38 males, 67 females) Kuwaiti patients with type 2 DM. The results were compared with creatinine clearance (Ccr), which was measured (mCcr) and estimated (eCcr) with the Cockroft-Gault formula, and correlated with 24-h urine protein and early morning urine albumin/creatinine excretion ratio. RESULTS: In patients with eCcr and mCcr results (n=51), eCcr and mCcr showed significant correlation with each other (r's=.86, P<.0001) with no significant difference between the two. In all patients (n=105), CC and B2M showed significant correlation with each other (r's=.82, P<.0001) and with serum creatinine concentration (r's=.77 and.84, respectively, P<.0001). Serum CC, B2M and creatinine showed significant (P<.001) inverse correlation with eCcr (r's=-.63, -.61 and -.76, respectively). Partial correlations after correcting for age and sex improved the correlation of serum creatinine with eCcr (r=-.81, P<.0001), but there was no significant change in the correlations of CC and B2M with eCcr (r=-.65, P<.0001 and r=-.62, P<.0001, respectively). Receiver operating characteristic (ROC) plots for serum CC, B2M and creatinine for detection of changes in the eCcr showed that the area under the ROC curve+/-S.E. is 0.897+/-0.119 for CC, 0.871+/-0.091 for B2M and 0.785+/-0.087 for serum creatinine. There was no statistically significant difference between the areas under the curve (AUC) for serum creatinine and CC (P=.07) and B2M (P=.12). CC had the highest sensitivity for detection of eCcr (<60 ml/min/1.73 m(2)) at routinely used cutoff values. CC was also the best discriminator when patients with normoalbuminuria were compared with patients with microalbuminuria. CONCLUSION: Although there is no significant difference in the overall diagnostic accuracies of CC, B2M and creatinine for the detection of changes in the GFR, CC is the most sensitive marker at routinely used cutoff values and would be more clinically useful than B2M or serum creatinine in diabetic patients.

Albuminuria↗
PubMed1997

Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy.

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder with onset between 6 and 13 years followed by variable progression to mental deterioration and cerebellar ataxia. It is a rare disorder but more common in Finland (1 in 20,000) and the western Mediterranean. Two point mutations in the cysteine proteinase inhibitor gene cystatin B (CSTB), proved that this gene is responsible for EPM1 (ref. 3). An extensive search in the CSTB gene revealed mutations accounting only for 14% of the 58 unrelated EPM1 alleles studied. Here we report that the majority of EPM1 alleles contain expansions of a dodecamer (12-mer) repeat located about 70 nucleotides upstream of the transcription start site nearest to the 5' end of the CSTB gene. Normal alleles contain 2 or 3 copies of this repeat whereas mutant alleles contain more than 60 such repeats and have reduced levels of CSTB messenger RNA in blood but not in cell lines. 'Premutation' CSTB alleles with 12-17 repeats show marked instability when transmitted to offspring.

Alleles↗
PubMed2005

Loss of lysosomal association of cystatin B proteins representing progressive myoclonus epilepsy, EPM1, mutations.

Loss-of-function mutations in the cystatin B (CSTB), a cysteine protease inhibitor, gene underlie progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1), characterized by myoclonic and tonic-clonic seizures, ataxia and a progressive course. A minisatellite repeat expansion in the promoter region of the CSTB gene is the most common mutation in EPM1 patients and leads to reduced mRNA levels. Seven other mutations altering the structure of CSTB, or predicting altered splicing, have been described. Using a novel monoclonal CSTB antibody and organelle-specific markers in human primary myoblasts, we show here that endogenous CSTB localizes not only to the nucleus and cytoplasm but also associates with lysosomes. Upon differentiation to myotubes, CSTB becomes excluded from the nucleus and lysosomes, suggesting that the subcellular distribution of CSTB is dependent on the differentiation status of the cell. Four patient mutations altering the CSTB polypeptide were transiently expressed in BHK-21 cells. The p.Lys73fsX2-truncated mutant protein shows diffuse cytoplasmic and nuclear distribution, whereas p.Arg68X is rapidly degraded. Two missense mutations, the previously described p.Gly4Arg affecting the highly conserved glycine, critical for cathepsin binding, and a novel mutation, p.Gln71Pro, fail to associate with lysosomes. These data imply an important lysosome-associated physiological function for CSTB and suggest that loss of this association contributes to the molecular pathogenesis of EPM1.

Animals↗
PubMed2006

Cystatin B: mutation detection, alternative splicing and expression in progressive myclonus epilepsy of Unverricht-Lundborg type (EPM1) patients.

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessive neurodegenerative disorder caused by mutations in the cystatin B gene (CSTB) that encodes an inhibitor of several lysosomal cathepsins. An unstable expansion of a dodecamer repeat in the CSTB promoter accounts for the majority of EPM1 disease alleles worldwide. We here describe a novel PCR protocol for detection of the dodecamer repeat expansion. We describe two novel EPM1-associated mutations, c.149G > A leading to the p.G50E missense change and an intronic 18-bp deletion (c.168+1_18del), which affects splicing of CSTB. The p.G50E mutation that affects the conserved QVVAG amino acid sequence critical for cathepsin binding fails to associate with lysosomes. This further supports the previously implicated physiological importance of the CSTB-lysosome association. Expression of CSTB mRNA and protein was markedly reduced in lymphoblastoid cells of the patients irrespective of the mutation type. Patients homozygous for the dodecamer expansion mutation showed 5-10% expression compared to controls. By combining database searches with RT-PCR we identified several alternatively spliced CSTB isoforms. One of these, CSTB2, was also present in mouse and was analyzed in more detail. In real-time PCR quantification, CSTB2 expression was less than 5% of total CSTB expression in all human adult and fetal tissues analyzed. In patients homozygous for the minisatellite mutation, the level of CSTB2 was reduced similarly to that of CSTB implicating regulation from the same promoter. The physiological significance of CSTB2 remains to be determined.

Alternative Splicing↗
PubMed2006

Cystatin C-based calculation of glomerular filtration rate in kidney transplant recipients.

Cystatin C (Cys C) has been shown to be an alternative marker of renal function. However, estimation of the glomerular filtration rate (GFR) based on Cys C has received little attention. Recently, several Cys C-based equations were developed in different patient cohorts. To date, the benefit of a Cys C-based GFR calculation in patients after renal transplantation (RTx) remains to be elucidated. We compared the diagnostic accuracy of three Cys C-based formulae (Larsson, Hoek, Filler which used an immunonephelometric method) with the results of the Modification of Diet in Renal Disease (MDRD) formula. GFR was measured by means of technetium-diethylenetriamine pentaacetic acid ((99m)Tc-DTPA) clearance in 108 consecutive patients after RTx. Correlation coefficients of all calculated GFR estimates with the true GFR were high but did not differ significantly from one another (0.83-0.87). The MDRD and Filler equations overestimated GFR significantly, whereas the Larsson equation significantly underestimated GFR. Bias of the Hoek formula was negligible. Precision of the Hoek (8.9 ml/min/1.73 m(2)) and Larsson equations (9.6 ml/min/1.73 m(2)) were significantly better than MDRD equations (11.4 ml/min/1.73 m(2); P< or =0.035 each). Accuracy within 30% of real GFR was 67.0 and 65.1% for the MDRD and Filler formulae, and 77.1% for the Larsson and Hoek formulae, respectively. Accuracy within 50% of true GFR for the Hoek formula (97.2%) was better than for the MDRD equations (85.3%). Cys C-based formulae may provide a better diagnostic performance than creatinine-based equations in GFR calculation after RTx.

Cystatin C↗
PubMed2001

Cystatin C, a cysteine protease inhibitor, is persistently up-regulated in neurons and glia in a rat model for mesial temporal lobe epilepsy.

Cystatin C (CSTC), a cysteine protease inhibitor, has been implicated in the processes of neuronal degeneration and repair of the nervous system. Using serial analysis of gene expression (SAGE), we recently identified CSTC as one of the genes that are overexpressed after electrically induced status epilepticus (SE). In the present study, Western blot analysis extended the SAGE results, showing increased CSTC protein in the hippocampus and entorhinal cortex. Immunocytochemistry revealed an increase in CSTC expression in glial cells, which was first apparent 24 h after onset of SE, and persisted for at least 3 months. Double immunolabelling confirmed that both reactive astrocytes, and activated microglia were CSTC immunopositive. Within the hippocampus, up-regulation was also observed in neuronal cells within one day after SE. Up-regulation was still present in hippocampal pyramidal cells and surviving interneurons of chronic epileptic rats (3-8 months post-SE). This study demonstrates that status epilepticus leads to a widespread and persistent up-regulation of CSTC in the hippocampus and entorhinal cortex, which may represent an intrinsic neuroprotective mechanism in the course of epileptogenesis that may counteract progression of the disease.

Animals↗
PubMed2002

Investigation of candidate genes for meat quality in dry-cured ham production: the porcine cathepsin B (CTSB) and cystatin B (CSTB) genes.

Excessive softness is a serious defect of dry cured hams which seems related to high activity of lysosomal cysteine proteinases, such as cathepsin B, in fresh pork muscles a few days after slaughtering. As it has been shown that cathepsin B activity has a moderate heritability in Italian Large White pigs we started a candidate gene approach to identify the gene(s) that affect(s) this parameter. Here, we studied two candidate genes: cathepsin B (CTSB) and cystatin B (CSTB). We amplified and sequenced porcine DNA fragments for these two genes that were used to identify polymorphisms by SSCP and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Four and two alleles were detected at the CTSB and CSTB loci, respectively. Sequencing of the CSTB alleles showed a missense mutation that changes a codon for aspartic acid into a codon for asparagine in exon 3 of the gene. Allele frequencies for the two loci differed among the pig breeds studied (Large White, Landrace, Duroc, Belgian Landrace, Hampshire, Piétrain, Meishan, Cinta Senese, Casertana, Calabrese and Nero di Sicilia). Linkage, somatic cell hybrid panel and radiation hybrid panel analyses assigned CTSB to porcine chromosome (Sscr) 14 and CSTB to Sscr 13. The markers identified at the CTSB and CSTB loci were used in association studies with several traits of economic importance including parameters that may indicate the suitability of pig meat to produce dry-cured hams. Significant associations were observed between CTSB and back-fat thickness and between CSTB and average daily gain. In this study, cathepsin B activity was not associated with the polymorphisms identified at the CTSB and CSTB loci.

Amino Acid Sequence↗
PubMed2002

Serum cystatin-C values in children by age and their fluctuation during dehydration.

BACKGROUND: Serum creatinine level (Cr) is extensively used as an index of glomerular filtration rate (GFR) with bedside patients. As serum Cr level differ by the muscle volume, the use of serum Cr as an index of GFR has long been considered problematic in children. METHODS: The subjects of this study were 135 healthy children aged from 1 to 15-years-old. As a pathological condition, the changes in serum cystatin C (Cys-C) in the children whose blood urea nitrogen exceeded 20 mg/dL during the acute stage of dehydration were also investigated. RESULTS: The mean serum Cys-C value was 0.67 +/- 0.19 mg/L on the whole. There was not any male-female difference. The mean serum Cys-C values of the 12 cases in the acute stage and the recovery stage were 0.61 +/- 0.12 mg/L and 0.64 +/- 0.14 mg/L, respectively, indicating no significant difference. CONCLUSION: Serum Cys-C is considered as a favorable index of GFR in children because it is not influenced by age and sex. As it is not influenced by the prerenal factors either, serum Cys-C is useful in children over 1-years-old.

Adolescent↗
PubMed2000

Seizures induce widespread upregulation of cystatin B, the gene mutated in progressive myoclonus epilepsy, in rat forebrain neurons.

Loss of function mutations in the gene encoding the cysteine protease inhibitor, cystatin B (CSTB), are responsible for the primary defect in human progressive myoclonus epilepsy (EPM1). CSTB inhibits the cathepsins B, H, L and S by tight reversible binding, but little is known regarding its localization and physiological function in the brain and the relation between the depletion of the CSTB protein and the clinical symptoms in EPM1. We have analysed the expression of mRNA and protein for CSTB in the adult rat brain using in situ hybridization and immunocytochemistry. In the control brains, the CSTB gene was differentially expressed with the highest levels in the hippocampal formation and reticular thalamic nucleus, and moderate levels in amygdala, thalamus, hypothalamus and cortical areas. Detectable levels of CSTB were found in virtually all forebrain neurons but not in glial cells. Following 40 rapidly recurring seizures evoked by hippocampal kindling stimulations, CSTB mRNA expression showed marked bilateral increases in the dentate granule cell layer, CA1 and CA4 pyramidal layers, amygdala, and piriform and parietal cortices. Maximum levels were detected at 6 or 24 h, and expression had reached control values at 1 week post-seizures. The changes of mRNA expression were accompanied by transient elevations (at 6-24 h) of CSTB protein in the same brain areas. These findings demonstrate that seizure activity leads to rapid and widespread increases of the synthesis of CSTB in forebrain neurons. We propose that the upregulation of CSTB following seizures may counteract apoptosis by binding cysteine proteases.

Animals↗
PubMed2003

Cystatin C colocalizes with amyloid-beta and coimmunoprecipitates with amyloid-beta precursor protein in sporadic inclusion-body myositis muscles.

Cystatin C (CC), an endogenous cysteine protease inhibitor, is accumulated within amyloid-beta (A beta) amyloid deposits in Alzheimer's disease (AD) brain and was proposed to play a role in the AD pathogenesis. Because the chemo-morphologic muscle phenotype of sporadic inclusion-body myositis (s-IBM) has several similarities with the phenotype of AD brain, including abnormal accumulation of A beta deposits, we studied expression and localization of CC in muscle biopsies of 10 s-IBM, and 16 disease- and five normal-control muscle biopsies. Physical interaction of CC with amyloid-beta precursor protein (A beta PP) was studied by a combined immunoprecipitation/immunoblotting technique in the s-IBM muscle biopsies and in A beta PP-overexpressing cultured human muscle fibers. In all s-IBM muscle biopsies, CC-immunoreactivity either colocalized with, or was adjacent to, the A beta-immunoreactive inclusions in 80-90% of the vacuolated muscle fibers, mostly in non-vacuolated regions of their cytoplasm. Ultrastructurally, CC immunoreactivity-colocalized with A beta on 6-10 nm amyloid-like fibrils and floccular material. By immunoblotting, CC expression was strongly increased in IBM muscle as compared to the controls. By immunoprecipitation/immunoblotting experiments, CC coimmunoprecipitated with A beta PP, both in s-IBM muscle and in A beta PP-overexpressing cultured normal human muscle fibers. Our studies (i) demonstrate for the first time that CC physically associates with A beta PP, and (ii) suggest that CC may play a novel role in the s-IBM pathogenesis, possibly by influencing A beta PP processing and A beta deposition.

Amyloid beta-Peptides↗