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  • Society for Neuroscience  (3)
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  • Society for Neuroscience  (3)
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  • 1
    Online Resource
    Online Resource
    A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth
    Society for Neuroscience ; 1994
    In:  The Journal of Neuroscience Vol. 14, No. 4 ( 1994-04-01), p. 2117-2127
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 14, No. 4 ( 1994-04-01), p. 2117-2127
    Abstract: The amyloid protein precursor (APP) of Alzheimer's disease is synthesized as an integral transmembrane protein that is released from cells in culture following proteolytic cleavage. The function of released APP is not known, although there is evidence that the protein may bind to components of the extracellular matrix (ECM). In the present study, substratum-bound APP stimulated neurite outgrowth in cultures of chick sympathetic and mouse hippocampal neurons. This effect was dependent upon the presence of substratum-bound heparan sulfate proteoglycans (HSPG). The effect of APP on neurite outgrowth was comparable to that of laminin. A 14 K N-terminal fragment of APP was found to bind heparin and a region close to the N-terminus of APP (residues 96–110) identified as a potential heparin-binding domain based on secondary structure predictions and molecular modeling. Mutagenesis of three basic residues (lysine-99, arginine-100, and arginine-102) resulted in a recombinant protein (APPhep) with decreased heparin-binding capacity. A peptide homologous to the heparin-binding domain was synthesized and found to bind strongly to heparin and to inhibit binding of 125I-labeled APP to heparin (IC50 approximately 10(- 7) M). The peptide blocked the effect of APP on neurite outgrowth (IC50 approximately 10(-7) M), whereas two other peptides homologous to other domains in APP had no effect. The results indicate that the binding of APP to HSPG in the ECM may stimulate the effects of APP on neurite outgrowth.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.14-04-02117.1994
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1994
    detail.hit.zdb_id: 1475274-8
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons
    Society for Neuroscience ; 1996
    In:  The Journal of Neuroscience Vol. 16, No. 3 ( 1996-02-01), p. 899-908
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 16, No. 3 ( 1996-02-01), p. 899-908
    Abstract: The aim of this study was to investigate the proteolytic processing of the amyloid precursor protein (APP) in polarized primary cultures of hippocampal neurons. We have used the Semliki Forest virus (SFV) vector to express human APP695 in hippocampal neurons, sympathetic ganglia, and glial cells. The latter two cells secrete little or no APP, whereas hippocampal neurons secrete two forms of APP695, which differ in sialic acid content and in their kinetic appearance in the culture medium. In addition, rat hippocampal neurons expressing human APP produced significant amounts of the 4 kDa peptide beta A4. After 3 hr of metabolic labeling, the relative amount of beta A4 peptide to total cellular APP was 5.3%. Fibroblasts expressing APP695 using the same SFV vector mainly produced a related 3 kDa p3 peptide, a nonamyloidogenic fragment. Remarkably, the hippocampal neurons also produced significant amounts of beta A4-containing C-terminal fragments (10–12 kDa) intracellularly. Radiosequencing showed that these fragments were created at a previously described beta-secretase cleavage site and at a cleavage site 12 residues from the N terminus of the beta A4 domain (Thr584 of APP695), which we named delta-cleavage. Based on the observation that mature hippocampal neurons produce two potentially amyloidogenic fragments and secrete substantial amounts of beta A4 when expressing human APP, our results strengthen the hypothesis that neurons play a central role in the process of beta A4 deposition in cases of Alzheimer's disease and in aged primates.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.16-03-00899.1996
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1996
    detail.hit.zdb_id: 1475274-8
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Association and release of the amyloid protein precursor of Alzheimer's disease from chick brain extracellular matrix
    Society for Neuroscience ; 1992
    In:  The Journal of Neuroscience Vol. 12, No. 11 ( 1992-11-01), p. 4143-4150
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 12, No. 11 ( 1992-11-01), p. 4143-4150
    Abstract: The amyloid protein precursor (APP) of Alzheimer's disease was found to bind saturably (Kd = 60 nM) to embryonic chick brain extracellular matrix (ECM). The binding of APP to ECM was not inhibited by 10 micrograms/ml heparin or heparan sulfate. However, pretreatment of cells with 1 mM 4-methylumbelliferyl-beta-D-xyloside, an inhibitor of proteoglycan biosynthesis, reduced the number of APP binding sites on the ECM by 80%. The binding of APP to ECM was also inhibited by pretreatment with chlorate, an inhibitor of glycan sulfation, and heparitinase, which digests the carbohydrate component of heparan sulfate proteoglycans. These results suggest that APP binds with high affinity to one or more heparan sulfate proteoglycans. Acidic and basic fibroblasts growth factor (FGF) also bound to chick ECM. When ECM was incubated with a protease associated with the enzyme AChE (AChE-AP), APP and acidic FGF were released intact from the matrix. The AChE-AP was at least 100-fold more potent in releasing APP from ECM than other trypsin-like proteases (trypsin, plasmin, thrombin). The action of the AChE-AP was inhibited by glia-derived nexin (protease nexin I) and by human brain APP at low nanomolar concentrations. These results suggest that in vivo an AChE-AP may cleave ECM proteins to regulate the availability of soluble APP or other factors bound to the ECM.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.12-11-04143.1992
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1992
    detail.hit.zdb_id: 1475274-8
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
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