Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.6.12 (chondroitinase)
 2,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:The role of heparan sulfate proteoglycans in the pathogenesis of Alzheimer's disease. 862 6

Human brain proteins were partially purified by using arginine-Sepharose 4B affinity chromatography, which traps proteins having an affinity to certain groups of arginine residue, such as serine proteases and zymogens. Bound proteins were analyzed for binding and cleavage related to the brain beta-amyloid precursor protein (APP). They were then further separated and isolated using a preparative gel system having a liquid-phase collection apparatus, using a non-denaturing gel system. Each fractionated protein was also analyzed for the above activity using natural APP. Among these, we found several fractions that bind preferentially to APP treated with chondroitinase ABC but not to intact APP, and that also generate particular beta-amyloid containing C-terminal peptides of APP via proteolysis. Our results suggest that sulfated glycoconjugates attached to APP play a role in the substrate specificity of APP for proteases, and also that the nature of natural APP processing mechanisms in vivo is very complex.
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PMID:A human brain proteolytic activity capable of cleaving natural beta-amyloid precursor protein is affected by its substrate glycoconjugates. 953 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.
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PMID:The 68K protease has beta-secretase-like activity for lymphocyte precursor protein but not for brain substrate. 1067 89

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.
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PMID:Perineuronal nets protect against amyloid beta-protein neurotoxicity in cultured cortical neurons. 1739 5