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  • Proceedings of the National Academy of Sciences  (6)
  • 1
    Online Resource
    Online Resource
    The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain
    Proceedings of the National Academy of Sciences ; 2002
    In:  Proceedings of the National Academy of Sciences Vol. 99, No. 3 ( 2002-02-05), p. 1365-1370
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 99, No. 3 ( 2002-02-05), p. 1365-1370
    Abstract: Proteolytic processing of the amyloid precursor protein by β-secretase generates C99, which subsequently is cleaved by γ-secretase, yielding the amyloid β peptide (Aβ). This γ-cleavage occurs within the transmembrane domain (TMD) of C99 and is similar to the intramembrane cleavage of Notch. However, Notch and C99 differ in their site of intramembrane cleavage. The main γ-cleavage of C99 occurs in the middle of the TMD, whereas the cleavage of Notch occurs close to the C-terminal end of the TMD, making it unclear whether both are cleaved by the same protease. To investigate whether γ-cleavage always occurs in the middle of the TMD of C99 or may also occur at the end of the TMD, we generated C99-mutants with an altered length of the TMD and analyzed their γ-cleavage in COS7 cells. The C terminus of Aβ and thus the site of γ-cleavage were determined by using monoclonal antibodies and mass spectrometry. Compared with C99-wild type (wt), most mutants with an altered length of the TMD changed the cleavage site of γ-secretase, whereas control mutants with mutations outside the TMD did not. Thus, the length of the whole TMD is a major determinant for the cleavage site of γ-secretase. Moreover, the C99-mutants were not only cleaved at one site but at two sites within their TMD. One cleavage site was located around the middle of the TMD, regardless of its actual length. An additional cleavage occurred within the N-terminal half of their TMD and thus at the opposite side of the Notch cleavage site.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.032395699
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2002
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons
    Proceedings of the National Academy of Sciences ; 1998
    In:  Proceedings of the National Academy of Sciences Vol. 95, No. 11 ( 1998-05-26), p. 6460-6464
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 95, No. 11 ( 1998-05-26), p. 6460-6464
    Abstract: The amyloid precursor protein (APP) plays a crucial role in the pathogenesis of Alzheimer’s disease. During intracellular transport APP undergoes a series of proteolytic cleavages that lead to the release either of an amyloidogenic fragment called β-amyloid (Aβ) or of a nonamyloidogenic secreted form consisting of the ectodomain of APP (APP sec ). It is Aβ that accumulates in the brain lesions that are thought to cause the disease. By reducing the cellular cholesterol level of living hippocampal neurons by 70% with lovastatin and methyl-β-cyclodextrin, we show that the formation of Aβ is completely inhibited while the generation of APP sec is unperturbed. This inhibition of Aβ formation is accompanied by increased solubility in the detergent Triton X-100 and is fully reversible by the readdition of cholesterol to previously depleted cells. Our results show that cholesterol is required for Aβ formation to occur and imply a link between cholesterol, Aβ, and Alzheimer’s disease.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.95.11.6460
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1998
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Mechanism of the cleavage specificity of Alzheimer’s disease γ-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein
    Proceedings of the National Academy of Sciences ; 1999
    In:  Proceedings of the National Academy of Sciences Vol. 96, No. 6 ( 1999-03-16), p. 3053-3058
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 96, No. 6 ( 1999-03-16), p. 3053-3058
    Abstract: Proteolytic processing of the amyloid precursor protein by β-secretase yields A4CT (C99), which is cleaved further by the as yet unknown γ-secretase, yielding the β-amyloid (Aβ) peptide with 40 (Aβ 40 ) or 42 residues (Aβ 42 ). Because the position of γ-secretase cleavage is crucial for the pathogenesis of Alzheimer’s disease, we individually replaced all membrane-domain residues of A4CT outside the Aβ domain with phenylalanine, stably transfected the constructs in COS7 cells, and determined the effect of these mutations on the cleavage specificity of γ-secretase (Aβ 42 /Aβ 40 ratio). Compared with wild-type A4CT, mutations at Val-44, Ile-47, and Val-50 led to decreased Aβ 42 /Aβ 40 ratios, whereas mutations at Thr-43, Ile-45, Val-46, Leu-49, and Met-51 led to increased Aβ 42 /Aβ 40 ratios. A massive effect was observed for I45F (34-fold increase) making this construct important for the generation of animal models for Alzheimer’s disease. Unlike the other mutations, A4CT-V44F was processed mainly to Aβ 38 , as determined by mass spectrometry. Our data provide a detailed model for the active site of γ-secretase: γ-secretase interacts with A4CT by binding to one side of the α-helical transmembrane domain of A4CT. Mutations in the transmembrane domain of A4CT interfere with the interaction between γ-secretase and A4CT and, thus, alter the cleavage specificity of γ-secretase.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.96.6.3053
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1999
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Transgenic Drosophila expressing human amyloid precursor protein show γ-secretase activity and a blistered-wing phenotype
    Proceedings of the National Academy of Sciences ; 1998
    In:  Proceedings of the National Academy of Sciences Vol. 95, No. 23 ( 1998-11-10), p. 13703-13708
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 95, No. 23 ( 1998-11-10), p. 13703-13708
    Abstract: The importance of the amyloid precursor protein (APP) in the pathogenesis of Alzheimer’s disease (AD) became apparent through the identification of distinct mutations in the APP gene, causing early onset familial AD with the accumulation of a 4-kDa peptide fragment (βA4) in amyloid plaques and vascular deposits. However, the physiological role of APP is still unclear. In this work, Drosophila melanogaster is used as a model system to analyze the function of APP by expressing wild-type and various mutant forms of human APP in fly tissue culture cells as well as in transgenic fly lines. After expression of full-length APP forms, secretion of APP but not of βA4 was observed in both systems. By using SPA4CT, a short APP form in which the signal peptide was fused directly to the βA4 region, transmembrane domain, and cytoplasmic tail, we observed βA4 release in flies and fly-tissue culture cells. Consequently, we showed a γ-secretase activity in flies. Interestingly, transgenic flies expressing full-length forms of APP have a blistered-wing phenotype. As the wing is composed of interacting dorsal and ventral epithelial cell layers, this phenotype suggests that human APP expression interferes with cell adhesion/signaling pathways in Drosophila , independently of βA4 generation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.95.23.13703
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1998
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    Intracellular and secreted Alzheimer β-amyloid species are generated by distinct mechanisms in cultured hippocampal neurons
    Proceedings of the National Academy of Sciences ; 1997
    In:  Proceedings of the National Academy of Sciences Vol. 94, No. 8 ( 1997-04-15), p. 4125-4130
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 8 ( 1997-04-15), p. 4125-4130
    Abstract: Cerebral plaques containing β-amyloid (βA4) represent an invariant pathological feature of Alzheimer disease (AD). βA4 is proteolytically generated from its parent molecule, amyloid precursor protein (APP). In nonneuronal cells βA4 has been shown to be secreted via a pH-sensitive and endocytosis-dependent pathway, and this process, when occurring in the brain, is considered to play an important role in AD. In neurons the mechanisms of βA4 production are not known. Here we have analyzed these mechanisms by expressing human APP and its mutant versions in hippocampal neurons using the Semliki forest virus system. We show that these cells initially generate two pools of βA4, an extracellular and an intracellular, and only the extracellular pool is produced via a pH-sensitive and endocytosis-dependent pathway. Thus, hippocampal neurons are able to utilize an alternate pathway to produce intracellular βA4. We also show that a common feature of two types of APP mutations (“Swedish” and “London”) implicated in early-onset AD is their increased production of C-terminally elongated βA4 (β 42 ), both intra- and extracellularly. Since neurons are the only cells that produce substantial levels of intracellular βA4 and also the main victims in AD, these findings may provide an important link between βA4 and neurodegeneration.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.94.8.4125
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1997
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 6
    Online Resource
    Online Resource
    The Amino-Acid Sequence of lac Repressor
    Proceedings of the National Academy of Sciences ; 1973
    In:  Proceedings of the National Academy of Sciences Vol. 70, No. 12 ( 1973-12), p. 3576-3580
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 70, No. 12 ( 1973-12), p. 3576-3580
    Abstract: The amino-acid sequence of lac repressor from Escherichia coli has been determined. The sequence contains 347 residues in the subunit single peptide chain. It shows no similarities with the sequences of histones or the known part of β-galactosidase.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.70.12.3576
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1973
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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