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  • Blackwell Science Ltd.  (2)
  • Springer  (2)
  • Blackwell Publishing Ltd  (1)
  • Wiley-Blackwell  (1)
  • 1995-1999  (6)
  • 1
    Electronic Resource
    Electronic Resource
    Intracellular Accumulation of Detergent-Soluble Amyloidogenic Aβ Fragment of Alzheimer's Disease Precursor Protein in the Hippocampus of Aged Transgenic Mice (1999)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 72 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: To study amyloid β-protein (Aβ) production and aggregation in vivo, we created two transgenic (Tg) mouse lines expressing the C-terminal 100 amino acids of human amyloid precursor protein (APP): Tg C100.V717F and Tg C100.WT. Western blot analysis showed that human APP-C100 and Aβ were produced in brain and some peripheral tissues and Aβ was produced in serum. Using antibodies specific for the Aβ C terminus we found that Tg C100.V717F produced a 1.6-fold increase in Aβ42/Aβ40 compared with Tg C100.WT. Approximately 30% of total brain Aβ (∼122 ng/g of wet tissue) was water-soluble. The remaining 70% of Aβ partitioned into the particulate fraction and was completely sodium dodecyl sulfate-soluble. In contrast, human Alzheimer's disease brain has predominantly sodium dodecyl sulfate-insoluble Aβ. Immunohistochemistry with an Aβ(5-8) antibody showed that Aβ or Aβ-containing fragments accumulated intracellularly in the hippocampus of aged Tg C100.V717F mice. The soluble Aβ levels in Tg brain are similar to those in normal human brain, and this may explain the lack of microscopic amyloid deposits in the Tg mice. However, this mouse model provides a system to study the intracellular processing and accumulation of Aβ or Aβ-containing fragments and to screen for compounds directed at the γ-secretase activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0722479.x
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  • 2
    Electronic Resource
    Electronic Resource
    The Hydrophobic Core Sequence Modulates the Neurotoxic and Secondary Structure Properties of the Prion Peptide 106-126 (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 neurodegeneration seen in spongiform encephalopathies is believed to be mediated by protease-resistant forms of the prion protein (PrP). A peptide encompassing residues 106-126 of human PrP has been shown to be neurotoxic in vitro. The neurotoxicity of PrP 106-126 appears to be dependent upon its adoption of an aggregated fibril structure. To examine the role of the hydrophobic core, AGAAAAGA, on PrP106-126 toxicity, we performed structure-activity analyses by substituting two or more hydrophobic residues for the hydrophilic serine residue to decrease its hydrophobicity. A peptide with a deleted alanine was also synthesized. We found all the peptides except the deletion mutant were no longer toxic on mouse cerebellar neuronal cultures. Circular dichroism analysis showed that the nontoxic PrP peptides had a marked decrease in β-sheet structure. In addition, the mutants had alterations in aggregability as measured by turbidity, Congo red binding, and fibril staining using electron microscopy. These data show that the hydrophobic core sequence is important for PrP106-126 toxicity probably by influencing its assembly into a neurotoxic structure. The hydrophobic sequence may similarly affect aggregation and toxicity observed in prion diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0731557.x
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  • 3
    Electronic Resource
    Electronic Resource
    Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione (1999)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 72 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Perturbations to glutathione (GSH) metabolism may play an important role in neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases. A primary function of GSH is to prevent the toxic interaction between free radicals and reactive transition metals such as copper (Cu). Due to the potential role of Cu in neurodegeneration, we examined the effect of GSH depletion on Cu toxicity in murine primary neuronal cultures. Depletion of cellular GSH with L-buthionine-[S,R]-sulfoximine resulted in a dramatic potentiation of Cu toxicity in neurons without effect on iron (Fe) toxicity. Similarly, inhibition of glutathione reductase (GR) activity with 1,3-bis(2-chloroethyl)-1-nitrosurea also increased Cu toxicity in neurons. To determine if the Alzheimer's amyloid-β (Aβ) peptide can affect neuronal resistance to transition metal toxicity, we exposed cultures to nontoxic concentrations of Aβ25-35 in the presence or absence of Cu or Fe. Aβ25-35 pretreatment was found to deplete neuronal GSH and increase GR activity, confirming the ability of Aβ to perturb neuronal GSH homeostasis. Aβ25-35 pretreatment potently increased Cu toxicity but had no effect on Fe toxicity. These studies demonstrate an important role for neuronal GSH homeostasis in selective protection against Cu toxicity, a finding with widespread implications for neurodegenerative disorders.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0722092.x
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  • 4
    Electronic Resource
    Electronic Resource
    Amyloid precursor-like protein 1 accumulates in neuritic plaques in Alzheimer’s disease (1997)
    Springer
    Acta neuropathologica 94 (1997), S. 519-524 
    Details
    ISSN: 1432-0533
    Keywords: Key words Alzheimer’s disease ; Amyloid ; precursor-like protein 1 ; Amyloid precursor protein ; Plaques
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The Alzheimer’s disease (AD) β-amyloid precursor protein (APP) and the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) are members of a superfamily of proteins that appear functionally related. Although APLPs are highly homologous to APP in the N- and C-terminal domains, they lack the βA4/amyloid peptide, i.e., the main constituent of neuritic plaques in AD. To assess a potential role of APLP1 in AD, we have determined its immunohistochemical distribution in human hippocampal formation, a structure which is strongly affected in AD, and compared it with APP immunoreactivity. There was a considerable overlap of APP and APLP1 regional expression patterns. Significant APLP1 immunoreactivity was observed in neuritic plaques. Large pyramidal neurons of the subiculum showed an accumulation of APLP1 protein in their dendritic compartment. Some astrocytes elicited perinuclear APLP1 staining, but this was observed in both AD and control brains. These findings raise the possibility that APLP1 may contribute to the pathogenesis of AD-associated neurodegeneration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004010050745
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  • 5
    Electronic Resource
    Electronic Resource
    Reverse relationship between β-amyloid precursor protein and β-amyloid peptide plaques in Down’s syndrome versus sporadic/familial Alzheimer’s disease (1999)
    Springer
    Acta neuropathologica 97 (1999), S. 113-118 
    Details
    ISSN: 1432-0533
    Keywords: Keywords Alzheimer’s disease ; Down’s syndrome ; β-Amyloid precursor protein ; β-Amyloid peptide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Strong genetic evidence has been accumulated in favor of a central role of β-amyloid precursor protein (APP) and β-amyloid peptide (βA4) in the pathogenesis of Alzheimer’s disease (AD). We employed four newly developed APP and βA4 antibodies and performed a comparative neuropathological study of patients with Down’s syndrome (DS), early-onset familial AD and sporadic AD to investigate the distribution of APP and βA4 plaque densities in the cerebral cortex of these disorders. Quantitative analysis of APP versus βA4 plaques revealed that brains with early-onset familial AD and sporadic AD showed significantly more βA4 plaques than brains with DS (P 〈 0.05). In contrast, APP plaques were more abundant in DS cerebral cortex (P 〈 0.02). These observations suggest that the development of pathological changes in DS brains does not parallel that observed in AD, which might be attributable to different causes in the pathogenesis of βA4 formation. A comparison of these disorders may be useful to further complement our knowledge of the mechanisms leading to plaque development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004010050963
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  • 6
    Electronic Resource
    Electronic Resource
    A synthetic substrate assay for the gamma-secretase of the β-A4 amyloid of alzheimer's disease (1995)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Peptide Science 1 (1995), S. 132-139 
    Details
    ISSN: 1075-2617
    Keywords: βA4 amyloid peptide ; radiometric assay ; transmembrane peptide ; reverse-phase TLC ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: γ-secretase, the endoprotease which releases the C-terminus of βA4 amyloid peptide, cleaves within the hydrophobic transmembrane domain of the amyloid precursor protein. In order to obtain a substrate for γ-secretase, a dodecapeptide which spans the cleavage site was synthesized, labelled with 125-iodine and conjugated to an agarose gel. A radiometric solid-phase assay was developed using this immobilized substrate. Peptide products were separated by reverse-phase HPLC and TLC to allow characterization of the cleavage site(s).
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/psc.310010205
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