Chondroitin sulfate proteoglycan form of cellular and cell-surface Alzheimer amyloid precursor (original) (raw)
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Chondroitin sulfate proteoglycan form of the Alzheimer's β-Amyloid precursor
Journal of Biological Chemistry
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 I...
Cellular Processing and Proteoglycan Nature of Amyloid Precursor Proteinsa
Annals of the New York Academy of Sciences, 1993
Amyloid P protein (PI& or AP), the main proteinaceous component of the amyloid depositions of the Alzheimer's brain, derives from the proteolytic processing of the amyloid precursor protein (APP). Cleavage of the amyloid precursor by at least two distinct secretase activities produces soluble secreted APP. The major secretase cleavage (site I) takes place between AP 16 and 17, while the minor cleavage (site 11) takes place after AD Lys 28 and may produce potentially amyloidogenic secreted APP. Pull-length cellular APP is cleaved by secretase intracellularly in the Trans-Golgi Network (TGN) or in post-Golgi vesicles. The resultant soluble APP is transported to the plasma membrane and exocytosed.
Chondroitin Sulfate Proteoglycans Are Associated with the Lesions of Alzheimer's Disease
Experimental Neurology, 1993
Chondroitin sulfate proteoglycans (CSPG) are extracellular matrix proteins inhibitory to neurite outgrowth in vitro and correlated with decreased neurite outgrowth after CNS injury. Previously, heparan sulfate proteoglycan and dermatan sulfate proteoglycan have been shown to be associated with senile plaques (SPs) and neurofibrillary tangles (NFTs) but CSPG was not. In an immunocytochemical study, three monoclonal antibodies to different sulfation states of the chondroitin glycosaminoglycan were used to localize CSPG in cases of Alzheimer's disease. Chondroitin 4-sulfate was found in both SPs and NFTs. An antibody to unsulfated chondroitin strongly immunostained intracellular NFTs and the dystrophic neurites of SPs. Chondroitin 6-sulfate was found in NFTs and the area around SPs. These results suggest that CSPG, in addition or as an alternative to ~-amyloid protein, could be responsible for the regression of neurites around senile plaques in Alzheimer's disease.
Amyloid precursor protein proteoglycan is increased after brain damage
Biochimica Et Biophysica Acta: Molecular Basis Of Disease, 1998
The b-amyloid peptide A b or A4 is produced by proteolytic cleavage from amyloid precursor protein APP. The progressive cerebral deposition of this peptide is one of the most important features of Alzheimer's disease. From the study of normal and transfected cells, two APP processing pathways have been proposed as physiological alternatives. One of these can produce A b or amyloidogenic peptides, whereas the second does not. However, it is not completely clear how APPs are post-translationally modified, proteolytically processed and metabolized in the brain. We report here that APPs Ž. also exist as proteoglycan, chondroitin-sulfate ChS. We have identified in normal rat brain a complex pool of 8 to 130 Ž. kDa ChS-core proteins. The main portion of these proteoglycan PGs APPs contains complete amyloidogenic sequence, suggesting a novel proteolytic processing of APP from the amino-terminal to the transmembrane region. This population appears augmented after brain damage. These findings may have significant implications in understanding the initial deposition and kinetics of amyloid aggregation in a pathological situation like Alzheimer's disease.
Journal of Biological Chemistry, 2001
Chondroitin sulfate (CS)-D and CS-E, which are characterized by oversulfated disaccharide units, have been shown to regulate neuronal adhesion, cell migration, and neurite outgrowth. CS proteoglycans (CSPGs) consist of a core protein to which one or more CS chains are attached via a serine residue. Although several brain CSPGs, including mouse DSD-1-PG/phosphacan, have been found to contain the oversulfated D disaccharide motif, no brain CSPG has been reported to contain the oversulfated E motif. Here we analyzed the CS chain of appican, the CSPG form of the Alzheimer's amyloid precursor protein. Appican is expressed almost exclusively by astrocytes and has been reported to have brain-and astrocyte-specific functions including stimulation of both neural cell adhesion and neurite outgrowth. The present findings show that the CS chain of appican has a molecular mass of 25-50 kDa. This chain contains a significant fraction (14.3%) of the oversulfated E motif GlcUA1-3GalNAc(4,6-O-disulfate). The rest of the chain consists of GlcUA1-3GalNAc(4-O-sulfate) (81.2%) and minor fractions of GlcUA1-3GalNAc and GlcUA1-3GalNAc(6-O-sulfate). We also show that the CS chain of appican contains in its linkage region the 4-O-sulfated Gal structure. Thus, appican is the first example of a specific brain CSPG that contains the E disaccharide unit in its sugar backbone and the 4-O-sulfated Gal residue in its linkage region. The presence of the E unit is consistent with and may explain the neurotrophic activities of appican.
Proteoglycans in the pathogenesis of Alzheimer's disease and other amyloidoses
Neurobiology of Aging, 1989
Proteoglycans in the pathogenesis of Alzheimer's disease and other amyloidoses. NEUROBIOL AGING 10(5) 481-497, 1989.-Proteoglycans and the amy loid P component are two constituents of amyloid that appear to be present regardless of the type of amyloid protein deposited, the extent of amyloid deposition and the tissue or organ involved. This article reviews the literature concerning proteoglycans and/or glycosaminoglycans in amyloidosis and describes recent studies which demonstrate their localization to the characteristic lesions of Alzheimer's disease and the amyloid plaques containing PrP protein in the prion diseases. Additionally, the possible interaction of proteoglycans with various amyloidogenic proteins, including the beta-amyloid protein in Alzheimer's disease is discussed. It is postulated that proteoglycans localized to a number of different amyloids play a common role in the pathogenesis of amyloidosis. Some of these hypothesized roles include 1) inducing amyloidogenic precursor proteins to form amyloid fibrils containing a predominant beta-pleated sheet structure, 2) influencing amyloid deposition to occur at specific anatomical sites within tissues and/or 3) aiding in prevention of amyloid degradation once amyloid has formed.
Neuroscience, 1999
In the human brain, the distribution of perineuronal nets occurring as lattice-like neuronal coatings of extracellular matrix proteoglycans ensheathing several types of non-pyramidal neurons and subpopulations of pyramidal cells in the cerebral cortex is largely unknown. Since proteoglycans are presumably involved in the pathogenesis of Alzheimer's disease, we analysed the distribution pattern of extracellular chondroitin sulphate proteoglycans in cortical areas, including primary motor, primary auditory and several prefrontal and temporal association areas, in normal human brains and in those showing neuropathological criteria of Alzheimer's disease. In both groups, neurons with perineuronal nets were most numerous in the primary motor cortex (approximately 10% in Brodmann's area 4) and in the primary auditory cortex as a representative of the primary sensory areas. Their number was lower in secondary and higher order association areas. Net-associated pyramidal cells oc...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1993
Extracellular matrix (ECM) is a secreted extracellular network. Few components of adult brain ECM are known. We have identified a new, large chondroitin sulfate proteoglycan (T1 antigen) that acts like a general ECM protein of brain. First, it is present throughout the brain; second, it has the properties of an extracellular protein; and third, it is extracted only under denaturing conditions. Immunocytochemical localization of the T1 antigen by light microscope shows it to be present throughout the rat brain in both white and gray matter. The T1 antigen outlines Purkinje and other large cells. No antigenicity is seen inside these cells. Biochemical evidence suggests that the T1 antigen is extracellular rather than cytosolic or intravesicular. The T1 antigen is disulfide-linked to two other proteins. Disulfide bonds are found only in extracellular or intravesicular proteins, not in intracellular cytosolic proteins. Moreover, the T1 antigen is probably not intravesicular. Unlike intr...
Molecular Interactions of Neural Chondroitin Sulfate Proteoglycans in the Brain Development
Archives of Biochemistry and Biophysics, 2000
Aggrecan family proteoglycans, phosphacan/ RPTP/, and neuroglycan C (NGC) are the major classes of chondroitin sulfate proteoglycan in the developing mammalian brain. A multidomain is a common structural feature of these proteoglycans which can interact with various molecules including growth factors, cell adhesion molecules, and extracellular matrix molecules. Individual proteoglycans are distributed in the developing brain in a distinct temporal and spatial pattern, suggesting that they are involved in distinct phases of the brain development through multiple molecular interactions. This review mainly summarizes recent studies on the involvement of these three classes of proteoglycan in cell-cell and cell-substratum interactions during the brain development. Their expressions and proposed functional roles in injured brains are also mentioned. In addition, this review briefly covers potential functions of other neural chondroitin sulfate proteoglycans such as decorin, testican, NG2 proteoglycan, and amyloid precursor protein (APP) in developing and injured brains.