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  • 1
    Electronic Resource
    Electronic Resource
    Expression of human FE65 in amyloid precursor protein transgenic mice is associated with a reduction in β-amyloid load (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 93 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: FE65 is an adaptor protein that interacts with the cytoplasmic tail of the amyloid precursor protein (APP). In cultured non-neuronal cells, the formation of the FE65-APP complex is a key element for the modulation of APP processing, signalling and β-amyloid (Aβ) production. The functions of FE65 in vivo, including its role in the metabolism of neuronal APP, remain to be investigated. In this study, transgenic mice expressing human FE65 were generated and crossbred with APP transgenic mice, known to develop Aβ deposits at 6 months of age. Compared with APP mice, APP/FE65 double transgenic mice exhibited a lower Aβ accumulation in the cerebral cortex as demonstrated by immunohistochemistry and immunoassay, and a lower level of APP-CTFs. The reduced accumulation of Aβ in APP/FE65 double transgenics, compared with APP mice, could be linked to the low Aβ42 level observed at 4 months of age and to the lower APP-CTFs levels. The present work provides evidence that FE65 plays a role in the regulation of APP processing in an in vivo model.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2005.03026.x
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  • 2
    Electronic Resource
    Electronic Resource
    A Novel Presenilin-2 Splice Variant in Human Alzheimer's Disease Brain Tissue (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: Mutations in the presenilin-1 (PS-1) and presenilin-2(PS-2) genes account for the majority of cases of early-onset familialAlzheimer's disease (AD). Alternative splicing forms of the PS-1 and PS-2 geneproducts have previously been reported in fibroblast and brain tissue fromboth familial and sporadic AD patients, as well as from normal tissues andcell lines. We demonstrate here unusual alternative splicing of the PS-2 genethat leads to the generation of mRNA lacking exon 5 in human brain tissue.This product was more frequently detected in brain tissue from sporadic ADpatients (70.0%; 21 of 30) than from normal age-matched controls (17.6%; threeof 17). In cultured neuroblastoma cells, this splice variant was generated inhypoxia but not under other forms of cellular stress. Hypoxia-mediatedinduction of this splice variant was blocked by pretreatment of neuroblastomacells with the protein synthesis inhibitor cycloheximide or antioxidants suchas N-acetylcysteine and diphenyl iodonium, suggesting that hypoxia-mediated oxidant stress might, at least in part, underlie the alternative splicing of PS-2 mRNA through de novo protein synthesis. Furthermore, the stable transfectants of this splice variant produced the N-terminal part of PS-2 protein (15 kDa) and were more susceptible to cellular stresses than control transfectants. These results suggest the possibility that altered presenilin gene products in stress conditions may also participate in the pathogenesis of AD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0722498.x
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  • 3
    Electronic Resource
    Electronic Resource
    Truncated beta-amyloid peptide species in pre-clinical Alzheimer's disease as new targets for the vaccination approach (2003)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 85 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Vaccination against human beta-amyloid peptide (Aβ) has been shown to remove the amyloid burden produced in transgenic mice overexpressing the mutated human amyloid precursor protein (APP) gene. For human beings, the efficiency of this therapeutic strategy has to take into account the specificities of human amyloid, especially at the early stages of ‘sporadic’ Alzheimer's disease (AD). Aβ 40/42 were previously quantified in tissues from our well-established brain bank, including non-demented individuals with both mild amyloid and tau pathologies, hence corresponding to the earliest stages of Alzheimer pathology. Herein, we have adapted a proteomic method combined with western blotting and mass spectrometry for the characterization of insoluble Aβ extracted in pure-formic acid. We demonstrated that amino-truncated Aβ species represented more than 60% of all Aβ species, not only in full blown AD, but also, and more interestingly, at the earliest stage of Alzheimer pathology. At this stage, Aβ oligomers were exclusively made of Aβ-42 species, most of them being amino-truncated. Thus, our results strongly suggest that amino-truncated Aβ-42 species are instrumental in the amyloidosis process. In conclusion, a vaccine specifically targeting these pathological amino-truncated species of Aβ-42 are likely to be doubly beneficial, by inducing the production of specific antibodies against pathological Aβ products that are, in addition, involved in the early and basic mechanisms of amyloidosis in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.01818.x
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  • 4
    Electronic Resource
    Electronic Resource
    Progressive decrease of amyloid precursor protein carboxy terminal fragments (APP-CTFs), associated with tau pathology stages, in Alzheimer's disease (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 81 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Amyloid precursor protein (APP) dysfunction is a key aetiologic agent in Alzheimer's disease (AD). The processing of this transmembrane protein generates carboxy terminal fragments (CTFs) upstream of β-amyloid peptide (Aβ) production. The physiologic significance of APP-CTFs is still poorly understood, as well as the relationship that could link APP dysfunction and tau pathology in familial and non-familial AD (non-FAD). In the present study, we have investigated the quantitative and qualitative changes of APP-CTFs in different brain areas of non-demented and demented patients from a prospective and multidisciplinary study. A significant decrease of the five APP-CTFs was observed, which correlated well with the progression of tau pathology, in most cases with infraclinical AD and AD, either familial or non-FAD. Furthermore, solubility properties and the ratio between the five bands were also modified, both in the Triton-soluble and/or -insoluble fractions. Together, we show here for the first time a modification directly observed on APP-CTFs upstream of Aβ products and its relationship with tau pathology, which could reflect the basic aetiological mechanisms of AD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.00901.x
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  • 5
    Electronic Resource
    Electronic Resource
    Effects of Aβ1−42 fibrils and of the tetrapeptide Pr-IIGL on the phosphorylation state of the τ-protein and on the α7 nicotinic acetylcholine receptor in vitro (2005)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 21 (2005), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In order to investigate the possible links connecting β-amyloid (Aβ) accumulation, τ-hyperphosphorylation and nicotinic receptor expression, rat embryonic primary hippocampal cultures were incubated with amyloidogenic peptides. Exposure to 0.5 µm fibrillar Aβ1−42 for 3 days caused retraction of dendrites, shrinkage of cell bodies and a decrease in the expression of microtubule-associated proteins 2b (MAP2b), without affecting the total number of neurons and their viability. No impact on the τ-phosphorylation sites Ser-202, Thr231/Ser235, Ser262 and Ser396/Ser404 was found. The total number of homomeric α7-nicotinic receptors (α7-nAChRs) and their affinity for [125I]α-bungarotoxin remained unaltered. Upon incubation with the putatively protective tetrapeptide propionyl–isoleucine–isoleucine–glycine–leucine (Pr-IIGL), an analogue of the region [31–34] of Aβ, cell bodies were swollen in the region of the apical dendrite. These morphological alterations, different from those elicited by Aβ1−42, did not involve MAP2 expression changes. In contrast to Aβ1−42, Pr-IIGL caused a massive hyperphosphorylation of the τ-protein at Ser-202 and at Ser396/Ser404. The total number of homomeric α7-nAChRs and their affinity for [125I]α-bungarotoxin were unaffected. In conclusion, the present results show a toxic effect of Aβ1−42 on the cytoskeletal structure at concentrations normally present in the brains of Alzheimer's disease patients, but raise some doubts about the role of Aβ1−42 fibrils as a direct trigger of τ-hyperphosphorylation. The tetrapeptide Pr-IIGL cannot be considered protective with regard to cell morphology. Although it prevents the Aβ1−42-induced retraction of dendrites, it exhibits other toxic properties. The homomeric α7-nAChRs were not affected either by Aβ1−42 incubation or by Pr-IIGL-induced τ-hyperphosphorylation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1460-9568.2005.03909.x
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  • 6
    Electronic Resource
    Electronic Resource
    Abnormal Tau phosphorylation of the Alzheimer-type also occurs during mitosis (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 83 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In Alzheimer's disease, neurofibrillary degeneration results from the aggregation of abnormally phosphorylated Tau proteins into filaments and it may be related to the reactivation of mitotic mechanisms. In order to investigate the link between Tau phosphorylation and mitosis, Xenopus laevis oocytes in which most of the M-phase regulators have been discovered were used as a cell model. The human Tau isoform htau412 (2+3–10+) was microinjected into prophase I oocytes that were then stimulated by progesterone that activate cyclin-dependent kinase pathways. Hyperphosphorylation of the Tau isoform, which is characterized by a decrease of its electrophoretic mobility and its labelling by a number of phosphorylation-dependent antibodies, was observed at the time of germinal vesicle breakdown. Surprisingly, Tau immunoreactivity, considered as typical of Alzheimer's pathology (AT100 and phospho-Ser422), was observed in meiosis II. Because meiosis II is considered as a mitosis-like phase, we investigated if our observation was also relevant to a neurone-like model. Abnormal Tau phosphorylation was detected in mitotic human neuroblastoma SY5Y cells overexpressing Tau. Regarding AT100-immunoreactivity and phospho-Ser422, we suggest that phosphatase 2A inhibition and a phosphorylation combination of mitotic kinases may lead to this Alzheimer-type phosphorylation. Our results not only demonstrate the involvement of mitotic kinases in Alzheimer-type Tau phosphorylation but also indicate that Xenopus oocyte could be a useful model to identify the kinases involved in this process.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.01143.x
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  • 7
    Electronic Resource
    Electronic Resource
    Alzheimer's : a correction (1992)
    [s.l.] : Nature Publishing Group
    Nature 356 (1992), S. 390-390 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] SIR - Lucotte and colleagues reported in Scientific Correspondence1 the occurrence of a mutation (valine for isoleucine) in the (3-amyloid precursor protein (APP) in a family in which both dementia and congophilic angiopathy occurs. G. A. and A. D. were responsible for the clinical ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/356390b0
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  • 8
    Electronic Resource
    Electronic Resource
    Tau marker? (1990)
    [s.l.] : Nature Publishing Group
    Nature 346 (1990), S. 22-22 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] SIR-The Alz-50 monoclonal antibody recognizes a neuronal antigen, termed A68, exclusively in Alzheimer brain tissue1. This antigen, of relative molecular mass 68,000 (68K), is also detected in the cerebrospinal fluid2 and in the olfactive epithelium from patients with Alzhei-mer's disease3, and it ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/346022a0
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  • 9
    Electronic Resource
    Electronic Resource
    Apolipoprotein E in Guamanian amyotrophic lateral sclerosis/ parkinsonism-dementia complex: genotype analysis and relationships to neuropathological changes (1996)
    Springer
    Acta neuropathologica 91 (1996), S. 247-253 
    Details
    ISSN: 1432-0533
    Keywords: Key words Amyotrophic lateral sclerosis ; Apolipoprotein E ; Guam ; Parkinsonism-dementia ; Tau proteins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Apolipoprotein E (Apo E) has been recently identified within amyloid deposits and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients. A strong association of the Apo E ε4 allele with higher risk of developing AD has also been reported. In the present study, the distribution of Apo E and the possible relationship between Apo E alleles and neuropathological alterations were analyzed in a series of Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) cases, a neurodegenerative condition characterized neuropathologically by widespread, severe neurofibrillary tangle formation but rare amyloid deposits. ApoE immunoreactivity was consistently observed in both type of lesions in these cases. Compared to tau protein immunoreactivity, there were generally fewer Apo E-immunoreactive neurofibrillary tangles, particularly in the deep layers of the neocortex and in the hippocampus. Genotype analysis revealed that the ε4 allele frequency was 5.9%, the ε3 allele frequency 88.2%, and the ε2 allele frequency 5.9% in this series. Recent data suggest that the Apo E4 variant may induce amyloidogenesis, while E2 could have a neuroprotective role. However, the rare Guamanian patients with amyloid deposits in cortical areas were not related to the ε4 allele, since all cases with senile plaques were ε3/ε3. In addition, compared to unaffected Guamanian cases and other Asian-Pacific populations previously reported, the observed low frequency of the ε2 allele in the present cases, which may be consistent with the notion that this allele, may represent a neuroprotective factor in several neurodegenerative disorders. The present data indicate that there is a strong interaction between Apo E deposition and neurofibrillary changes in Guamanian ALS-PDC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004010050422
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