Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:APRD00216 (ABC)
 8,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Skin fibroblasts lines established from patients with Alzheimer's disease and old normal individuals were cultured with 35S-sodium sulfate and 3H-glucosamine. Proteoglycans were isolated and characterized. Sulfate incorporation into proteoglycans increased in Alzheimer's disease fibroblasts relative to normal controls. These increases changed the ratio of chondroitin sulfate to heparan sulfate proteoglycan from 1.4 to 1.7 (p = 0.0012) and decreased the ratio of cell to medium proteoglycans from 0.32 to 0.26 in normal and Alzheimer fibroblasts (p = 0.006), respectively. HPLC analysis of the disaccharides produced by chondroitinase ABC revealed no differences in composition between proteoglycans of Alzheimer and normal fibroblasts in either the cell or medium fraction. However, analysis of disaccharides produced by heparinase plus heparitinase showed differences in composition in the medium but not the cell fraction. delta UA-GlcNS was increased by 30% while delta UA-GlcNS-6S was reduced by 40% in Alzheimer's disease.
 ...
PMID:Characterization of proteoglycans in Alzheimer's disease fibroblasts. 159 Jul 92

The Alzheimer's amyloid beta protein is derived from a family of membrane glycoproteins termed amyloid precursor proteins (APP). Here we show that APP exists as the core protein of a chondroitin sulfate (CS) proteoglycan, ranging in apparent molecular size from 140 to 250 kDa, secreted by glial cell line C6. After partial purification on ion-exchange and gel chromatography, the secreted APP proteoglycan was recognized on Western blots by several antibodies specific to different regions of APP. Chondroitinase AC or ABC treatment of our samples completely eliminated the high molecular weight proteoglycan with a concomitant increase in the APP protein. This digested product reacted with an anti-stub antibody which recognizes 4-sulfated disaccharide. Sequencing of the N terminus of the core protein of this CS proteoglycan yielded 18 residues identical to the N terminus sequence of the mature APP. Quantitative analysis showed that, in this cell line, about 90% of the secreted nexin II form of APP occurs in the proteoglycan form, suggesting that the CS chains have a role in the biological function of this protein. The close proximity of two consensus CS attachment sites to both the N terminus of the amyloid beta protein and the secretase cleavage site, suggests that the CS chains may affect the proteolysis of APP and production of the amyloid beta protein.
 ...
PMID:Chondroitin sulfate proteoglycan form of the Alzheimer's beta-amyloid precursor. 162 83

Brain sections from Alzheimer's disease (AD) patients and controls were treated with basic fibroblast growth factor (bFGF) and then immunostained with anti-bFGF. Additional sections were treated with biotinylated bFGF without using the anti-bFGF. Labelling was visualized by the ABC method. Both protocols above intensely labelled neurofibrillary tangles, senile plaques and amyloidotic vessels in AD brains. Omission of the bFGF treatment abolished the staining of the AD lesions. The pretreatment of sections with heparitinase also reduced their staining. These results indicate that AD lesions contain bFGF-binding sites and that the chemical substrate for bFGF binding to AD lesions was heparan sulfate.
 ...
PMID:The binding of basic fibroblast growth factor to Alzheimer's neurofibrillary tangles and senile plaques. 171 56

Since apolipoprotein E immunoreactivity has been shown in senile plaque and neurofibrillary tangle in Alzheimer's disease brains, we performed immunohistochemistry to examine whether or not apolipoprotein B (apoB) was associated with these abnormal structures. Sections of hippocampus from formalin-fixed, paraffin-embedded tissues were immunostained with a standard ABC method. We found that apoB immunoreactivity was associated with amyloid both in senile plaques and cerebral vessels and with neurofibrillary tangles. Positive staining was abolished with pretreatment of the antibody with the human apoB. It is suggested that the potential blood-brain barrier impairment may allow an increasing amount of serum proteins, such as apoB, to penetrate the brain and bind to these AD-associated abnormal structures.
 ...
PMID:[Apolipoprotein B immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in senile dementia of Alzheimer type]. 176 57

Several degenerative diseases of the central nervous system are characterized by the presence of neuronal inclusions. One of these inclusions, neurofibrillary tangles in Alzheimer's disease, has been shown to contain ubiquitin that belongs to a group of proteins known as heat shock proteins. Subsequent studies revealed that ubiquitin is also associated with various neuronal inclusions including Lewy bodies, Pick bodies and hyaline inclusions. Very recently, ubiquitin has been found also to be associated with glial inclusions that are unique to multiple system atrophy. The close association of ubiquitin with varying cellular inclusions, together with its function in the proteolytic process, raised the hypothesis that ubiquitin may be involved in the degradation of abnormal proteins appearing in the damaged neurons and glial cells. In central nervous system, a group of heat shock proteins collectively known as HSP 70 is also present which is constitutive and/or inducible. Since HSP 70 has been suspected to play a crucial role degradation and repair of abnormal intracellular proteins, we hypothesized that HSP 70 may be associated with those inclusions, as the case with ubiquitin. To test this we performed immunohistochemical studies on brain tissues from patients with various neurodegenerative conditions by using specific polyclonal antibody to HSP 70. Brain tissues were obtained at autopsy from each three patients with Alzheimer's disease, Pick's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and multiple system atrophy. Tissues were fixed in buffered formalin and embedded in paraffin. Immunostaining was performed by the standard ABC method using diaminobenzidine as a chromogen. Sections were lightly stained with hematoxylin. Polyclonal antibodies were raised in rabbits against mouse HSP 70.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[HSP 70 is associated with abnormal cytoplasmic inclusions characteristic of neurodegenerative diseases]. 205 24

The hallmark of Alzheimer's disease (AD) is the deposition of amyloid plaques and neurofibrillary tangles in the brain. The relationship between amyloid deposition and the cognitive deficit is still unclear. The amyloid beta A4 protein is produced by proteolytic cleavage of the amyloid protein precursor (APP). Very little is known about the normal function of APP and the role the protein may play in pathogenesis. Several studies have shown that APP is important for the regulation of neurite outgrowth. Our studies support these findings and indicate that the neurite outgrowth-promoting effects of APP are stimulated by an interaction between APP and specific proteoglycans. Using site-directed mutagenesis, a heparan sulfate binding site which mediates this effect has been mapped to the N-terminus of APP (residues 96-110, HBD-1). A peptide homologous to HBD-1 blocks the trophic effects of APP in cell culture. To purify specific proteoglycans which stimulate the action of APP, an affinity column was constructed using a biotinylated peptide homologous to HBD-1 coupled to streptavidin-agarose. Two proteoglycans were isolated from a crude brain cell conditioned medium by affinity chromatography. The purified proteoglycans bound APP saturably with high affinity and stimulated the action of APP on neurite outgrowth from chick sympathetic neurons. Digestion of the proteoglycan fraction with heparitinase I or chondroitinase ABC demonstrated the presence of two major proteins, a heparan sulfate proteoglycan with a core protein of 63-67 kD molecular mass and a chondroitin sulfate proteoglycan with a core protein of 100-110 kD molecular mass. The results demonstrate that APP binds to at least two proteoglycans and that this interaction may regulate the trophic effects of the protein. The interaction of specific APP-binding proteoglycans with amyloid plaques may disturb the normal function of APP and contribute to the neuritic degeneration that is commonly seen around the amyloid plaque cores.
 ...
PMID:The role of heparan sulfate proteoglycans in the pathogenesis of Alzheimer's disease. 862 6

Processing and metabolism of beta-amyloid precursor protein (APP) and generation of a variety of beta-amyloid (Abeta) peptides in the human brain is essentially associated with pathophysiology of Alzheimer's disease (AD). APP degradation activity of the 68 kDa serine protease, which was originally prepared from familial AD lymphoblastoid cells and harbors beta-secretase-like activity, was analyzed by Western blot using anti Abeta 1/40 antibody and anti APP cytoplasmic domain (CT) antibody. Native lymphocyte APP (LAPP) prepared from normal or AD-derived lymphoblastoid cells was degraded by the protease, generating a 16 kDa Abeta-bearing C-terminal fragment of APP. N-terminal amino acid sequencing of the fragment indicated that the protease cleaves LAPP at the Abeta-N-terminus. When the LAPP was treated with chondroitinase ABC prior to proteolysis, the activity to generate the fragment was inhibited, but pretreatment with heparitinase resulted in no effect. Native hippocampal APP prepared from normal brain, however, did not generate the 16 kDa peptide by the protease treatment. These results suggest that the process of APP degradation and Abeta-peptides generation, including beta-secretase activity, is associated with tissue specificity of both APP substrate and proteases. They also indicate that sulfated glycoconjugates attached to a portion of APP isoforms may play a role as a molecular determinant in the proteolysis.
 ...
PMID:The 68K protease has beta-secretase-like activity for lymphocyte precursor protein but not for brain substrate. 1067 89

Proteoglycans (PGs) have been suggested to work as receptors in lipoprotein uptake mechanisms. An interaction between apolipoprotein E (apoE) and glucosaminoglycans (GAG), polysaccharides linked to proteoglycans, has been proposed in this pathway. At the same time, proteoglycans, apoE as well as lipoprotein receptors have been reported to be constituents of amyloid plaques, one hallmark of Alzheimer's disease. With this study, we are the first to investigate the interaction between beta very low density lipoprotein (beta-VLDL) and a neuronal highly abundant GAG, chondroitin sulphate (CS), comparing hippocampal neurons, expressing high levels of low density lipoprotein receptor related protein (LRP) and U373 astrocytoma cells, highly positive for the low density lipoprotein receptor (LDLR). We were able demonstrate that degradation of chondroitin sulphate proteoglycans (CSPGs) with chondroitinase ABC resulted in reduced (125)I-beta-VLDL uptake. We showed that externally added CSs compete with internalization of beta-VLDL. The effect was found to be dose-dependent, but was influenced neither by cell type, nor receptor type. The position of sulphation of added CSs showed only a slight influence. The data generated suggested an interaction between apolipoproteins and soluble CSs; therefore, 3H-cholesterol linked to apoE was coadministered with CSs to the cells. The results revealed that apoE bound, but no unbound cholesterol, was reduced in cellular internalization, suggesting that CSPGs may be involved in lipoprotein uptake in the intact brain, mediated, at least in part, by apoE.
 ...
PMID:Role of chondroitin sulphate in the uptake of beta-VLDL by brain cells. 1619 Aug 94

A recent study demonstrated a significant genetic association between the ATP-binding cassette transporter A2 (ABCA2) and the risk for Alzheimer's disease (AD) in a large Caucasian sample. The rare T allele of the synonymous exonic single nucleotide polymorphism (SNP) rs908832 was overrepresented in early-onset AD patients as compared to cognitively healthy controls. Here we confirm the association of rs908832 with AD in a Western European population (n = 291, P = 0.008). In a second sample from Southern Europe, rs908832 was not associated with AD. Interestingly, rs908832 was not polymorphic in a Japanese sample. Furthermore, rs908832 was not associated with either serum cholesterol levels or with the risk for coronary artery disease, but seemed to be related to cholesterol levels in the cerebrospinal fluid. These data suggest that ABCA2 may exert population-dependent effects on the genetic risk for sporadic AD and support a role of ABC lipid transporters in the pathogenesis of this disease.
 ...
PMID:Ethnicity-dependent genetic association of ABCA2 with sporadic Alzheimer's disease. 1675 60

Perineuronal nets (PNs) consisting of chondroitin sulfate proteoglycans (CSPGs) and hyaluronic acid are associated with distinct neuronal populations in mammalian brain. Cortical areas abundant in PNs have been known to be less affected by neurotoxicity in human Alzheimer's disease. In the present study, we examined whether PNs protect the neurotoxicity caused by amyloid beta-protein (Abeta), a major constituent of senile plaques in Alzheimer's disease using cortical neurons of dissociated culture. Double labeling experiments using confocal microscopy showed that the neurons associated with PNs were visualized with the anti-CSPG antibody in dissociated cortical culture. The analysis of reverse transcription-polymerase chain reaction revealed that mRNA expression of chondroitin sulfotransferases, CSPG-specific enzymes, was detected in neuronal culture, indicating that cultured cortical neurons are able to synthesize CSPGs and construct PNs structure. The treatment of Abeta1-42 showed significant neurotoxicity on PNs-free cortical neurons, however, it did not reveal neurotoxicity on PNs-associated neurons. Moreover, it was shown that the treatment of Abeta1-42 was able to kill PNs-associated neurons after the removal of chondroitin sulfate (CS) glycosaminoglycans with chondroitinase ABC. The treatment of glutamate killed not only PNs-free cortical neurons but also PNs-associated neurons. These results suggest that CS glycosaminoglycans on PNs are responsible for protecting neurons from Abeta1-42 neurotoxicity.
 ...
PMID:Perineuronal nets protect against amyloid beta-protein neurotoxicity in cultured cortical neurons. 1739 5


1 2 3 4 5 6 Next >>