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  • 1
    Electronic Resource
    Electronic Resource
    Low-density lipoprotein receptor-related protein levels and endocytic function are reduced by overexpression of the FE65 adaptor protein, FE65L1 (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 82 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The FE65 adaptor protein family was identified in two-hybrid screens as proteins that bind the cytoplasmic domain of the amyloid precursor protein (APP). Studies have shown that FE65 binding to APP modulates APP processing. Increased levels of α-secretase derived secreted APP (APPsα) and β-amyloid (Aβ) were recovered from conditioned media upon FE65L1 or FE65 overexpression. These effects were associated with an increase in the ratio of mature/immature APP and increased cell-surface APP. FE65 has also been reported to bind low-density lipoprotein receptor-related protein (LRP). Here we show that FE65L1 overexpression results in decreased LRP steady state levels, LRPs, and LRP endocytic receptor function. These changes in LRP protein levels are not due to decreased transcription of LRP. Furthermore, pulse/chase experiments demonstrate that changes in LRP protein only occurred 12–18 h after translation. We conclude that the decreases in LRP levels likely reflect routing of LRP away from the cell surface into a degradative pathway. Previous studies suggested that LRP plays an important role for Aβ production of Kunitz protease inhibitor forms of APP in the endocytic pathway. These data show that FE65L1 can differentially affect the metabolic fate of APP and LRP. In addition, these data suggest that the LRP decrease observed in FE65L1 overexpressing cells may in part contribute to altered APP processing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.01009.x
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  • 2
    Electronic Resource
    Electronic Resource
    Staurosporine-Induced Activation of Caspase-3 Is Potentiated by Presenilin 1 Familial Alzheimer's Disease Mutations in Human Neuroglioma Cells (1999)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 73 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : Familial Alzheimer's disease (FAD) mutant forms of presenilin 1 (PS1) and 2 have been shown to sensitize cells to apoptotic cell death. Here we explore the effects of FAD mutant forms of PS1 on caspase activation during apoptosis. We show that caspase activation leads to increased generation of alternative C-terminal fragments (CTFs) from mutant as compared to wild-type (wt) PS1. For this purpose, very low expression levels of wt, A246E, L286V, and ΔE10 FAD mutant PS1 proteins in stably transfected human H4 neuroglioma cells were used to avoid artifactual induction of spontaneous apoptosis due to overexpression of PS1. Staurosporine treatment of these cells resulted in increased cell death and up to a 10-fold increase in caspase-3 activation in mutant versus wt PS1-expressing cell lines. Correspondingly, relative levels of caspase-cleaved PS1 CTFs were increased by five-to sixfold in the FAD mutant versus wt PS1 cells. Elevated caspase activation and caspase cleavage of FAD mutant PS1 suggest the possibility of either a direct proapoptotic effect of mutant PS1 or interference of mutant PS1 with antiapoptotic effects of wt PS1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0732278.x
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  • 3
    Electronic Resource
    Electronic Resource
    hFE65L Influences Amyloid Precursor Protein Maturation and Secretion (1999)
    Oxford UK : Blackwell Science Ltd
    Journal of neurochemistry 73 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : The amyloid precursor protein (APP) is processed in the secretory and endocytic pathways, where both the neuroprotective α-secretase-derived secreted APP (APPsα) and the Alzheimer’s disease-associated β-amyloid peptide are generated. All three members of the FE65 protein family bind the cytoplasmic domain of APP, which contains two sorting signals, YTS and YENPTY. We show here that binding of APP to the C-terminal phosphotyrosine interaction domain of hFE65L requires an intact YENPTY clathrin-coated pit internalization sequence. To study the effects of the hFE65L/APP interaction on APP trafficking and processing, we performed pulse/chase experiments and examined APP maturation and secretion in an H4 neuroglioma cell line inducible for expression of the hFE65L protein. Pulse/chase analysis of endogenous APP in these cells showed that the ratio of mature to total cellular APP increased after the induction of hFE65L. We also observed a threefold increase in the amount of APPsα recovered from conditioned media of cells overexpressing hFE65L compared with uninduced controls. The effect of hFE65L on the levels of APPsα secreted is due neither to a simple increase in the steady-state levels of APP nor to activation of the protein kinase C-regulated APP secretion pathway. We conclude that the effect of hFE65L on APP processing is due to altered trafficking of APP as it transits through the secretory pathway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0730985.x
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  • 4
    Electronic Resource
    Electronic Resource
    Characterization of Copper Interactions with Alzheimer Amyloid β Peptides (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 75 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Cu and Zn have been shown to accumulate in the brains of Alzheimer's disease patients. We have previously reported that Cu2+ and Zn2+ bind amyloid β (Aβ), explaining their enrichment in plaque pathology. Here we detail the stoichiometries and binding affinities of multiple cooperative Cu2+-binding sites on synthetic Aβ1-40 and Aβ1-42. We have developed a ligand displacement technique (competitive metal capture analysis) that uses metal-chelator complexes to evaluate metal ion binding to Aβ, a notoriously self-aggregating peptide. This analysis indicated that there is a very-high-affinity Cu2+-binding site on Aβ1-42 (log Kapp = 17.2) that mediates peptide precipitation and that the tendency of this peptide to self-aggregate in aqueous solutions is due to the presence of trace Cu2+ contamination (customarily ∼0.1 μM). In contrast, Aβ1-40 has much lower affinity for Cu2+ at this site (estimated log Kapp = 10.3), explaining why this peptide is less self-aggregating. The greater Cu2+-binding affinity of Aβ1-42 compared with Aβ1-40 is associated with significantly diminished negative cooperativity. The role of trace metal contamination in inducing Aβ precipitation was confirmed by the demonstration that Aβ peptide (10 μM) remained soluble for 5 days only in the presence of high-affinity Cu2+-selective chelators.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0751219.x
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  • 5
    Electronic Resource
    Electronic Resource
    APP substitutions V715F and L720P alter PS1 conformation and differentially affect Aβ and AICD generation (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 95 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The 37–43 amino acid Aβ peptide is the principal component of β-amyloid deposits in Alzheimer's disease (AD) brain, and is derived by serial proteolysis of the amyloid precursor protein (APP) by β- and γ-secretase. γ-Secretase also cleaves APP at Val50 in the Aβ numbering (ε cleavage), resulting in the release of a fragment called APP intracellular domain (AICD). The aim of this study was to determine whether amino acid substitutions in the APP transmembrane domain differentially affect Aβ and AICD generation. We found that the APPV715F substitution, which has been previously shown to dramatically decrease Aβ40 and Aβ42 while increasing Aβ38 levels, does not affect in vitro generation of AICD. Furthermore, we found that the APPL720P substitution, which has been previously shown to prevent in vitro generation of AICD, completely prevents Aβ generation. Using a fluorescence resonance energy transfer (FRET) method, we next found that both the APPV715F and APPL720P substitutions significantly increase the distance between the N- and C-terminus of presenilin 1 (PS1), which has been proposed to contain the catalytic site of γ-secretase. In conclusion, both APPV715F and APPL720P change PS1 conformation with differential effects on Aβ and AICD production.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2005.03381.x
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  • 6
    Electronic Resource
    Electronic Resource
    ALZHEIMER'S DISEASE: Genetic Studies and Transgenic Models (1998)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Genetics 32 (1998), S. 461-493 
    Details
    ISSN: 0066-4197
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Abstract Recent advances in a variety of areas of research, particularly in genetics and in transgenic (Tg)/gene targeting approaches, have had a substantial impact on our understanding of Alzheimer's disease (AD) and related disorders. After briefly reviewing the progress that has been made in diagnostic assessments of patients with senile dementia and in investigations of the neuropathology of AD, we discuss some of the genes/proteins that are causative or risk factors for this disease, including those encoding amyloid precursor protein, presenilin 1 and 2, and apolipoprotein E. In addition, we comment on several potential new candidate loci/genes. Subsequently, we review selected recent reports of analyses of a variety of lines of Tg mice that show several neuropathological features of AD, including Abeta-amyloid deposits and dystrophic neurites. Finally, we discuss the several important issues in future investigations of Tg mice, with particular emphasis on the influences of genetic strains on phenotype, especially behavior, and strategies for making new models of neurodegenerative disorders. We believe that investigations of these Tg models will (a) enhance understanding of the relationships between impaired performance on memory tasks and the pathological/biochemical abnormalities in brain, (b) help to clarify pathogenic mechanisms in vivo, (c) lead to identification of new therapeutic targets, and (d) allow testing of new treatment strategies first in mice and then, if successful, in humans with AD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.genet.32.1.461
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  • 7
    Electronic Resource
    Electronic Resource
    Search for the Genes Responsible for Familial Alzheimer's Disease (1993)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 695 (1993), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Notes: Inherited or Familial Alzheimer's Disease (FAD) has clearly been shown to be a genetically heterogeneous disorder. Mutations in the gene on chromosome 21 encoding the β—amyloid protein precursor (APP) have been shown to be linked to 2–3% of FAD kindreds examined around the world. A late onset FAD locus has been mapped to a region of chromosome 19 in which a recently isolated APP-like gene, APLP1 has also been localized, making this gene a strong candidate to harbor a late-onset FAD defect. More recently, a major FAD locus has been mapped to the long arm of chromosome 14. The chromosome 14 locus appears to be mainly linked to the gene defect in early onset FAD pedigrees. Besides the FAD loci on chromosome 21, 19, and 14, at least two other loci must exist since the gene defect in some early- and late-onset FAD pedigrees do not appear to segregate with markers from any of these autosomes. As different gene defects responsible for various forms of FAD are discovered, perhaps, a common basis for the etiology of this devastating disorder can be discerned.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1993.tb23053.x
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  • 8
    Electronic Resource
    Electronic Resource
    Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database (2007)
    [s.l.] : Nature Publishing Group
    Nature genetics 39 (2007), S. 17-23 
    Details
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly difficult to follow, much less interpret. We have created a publicly available, continuously updated ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/ng1934
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  • 9
    Electronic Resource
    Electronic Resource
    Of calcium, caspases, and cognitive decline (1998)
    [s.l.] : Nature America Inc.
    Nature medicine 4 (1998), S. 1127-1128 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] A calcium-binding protein interacts with the presenilins, modulating their proteolytic processing (pages 1177–1181). ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/2622
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  • 10
    Electronic Resource
    Electronic Resource
    An α-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease (reply) (1999)
    [s.l.] : Nature America Inc.
    Nature genetics 22 (1999), S. 21-22 
    Details
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] In reply—We are pleased by Rudrasingham and colleagues' confirmation in the NIA family sample of our finding of a genetic association between the gene encoding α-2-macroglobulin (A2M) and Alzheimer disease (AD) in the NIMH sample. We also do not find it surprising that the ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/8732
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