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  • 1
    Online Resource
    Online Resource
    Genes contributing to prion pathogenesis
    Microbiology Society ; 2008
    In:  Journal of General Virology Vol. 89, No. 7 ( 2008-07-01), p. 1777-1788
    Details
    In: Journal of General Virology, Microbiology Society, Vol. 89, No. 7 ( 2008-07-01), p. 1777-1788
    Abstract: Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP C ) to a misfolded, pathogenic isoform (PrP Sc ). Prion inoculation experiments in mice expressing homologous PrP C molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes, because their products either colocalize with PrP, are associated with Alzheimer's disease, are elevated during prion disease, or function in PrP-mediated signalling, PrP glycosylation, or protein maintenance. Whereas some of the candidates tested may have a role in the normal function of PrP C , our data show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein ( App ) or interleukin-1 receptor, type I ( Il1r1 ), and transgenic overexpression of human superoxide dismutase 1 ( SOD1 ) prolonged incubation times by 13, 16 and 19 %, respectively.
    Type of Medium: Online Resource
    ISSN: 0022-1317 , 1465-2099
    URL: Article
    DOI: 10.1099/vir.0.2008/001255-0
    RVK:
    XA 53770
    RVK:
    WA 15000
    Language: English
    Publisher: Microbiology Society
    Publication Date: 2008
    detail.hit.zdb_id: 2007065-2
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Developmental Pathogenicity of 4-Repeat Human Tau Is Lost with the P301L Mutation in Genetically Matched Tau-Transgenic Mice
    Society for Neuroscience ; 2020
    In:  The Journal of Neuroscience Vol. 40, No. 1 ( 2020-01-02), p. 220-236
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 40, No. 1 ( 2020-01-02), p. 220-236
    Abstract: Tau is a microtubule-associated protein that becomes dysregulated in a group of neurodegenerative diseases called tauopathies. Differential tau isoforms, expression levels, promoters, and disruption of endogenous genes in transgenic mouse models of tauopathy make it difficult to draw definitive conclusions about the biological role of tau in these models. We addressed this shortcoming by characterizing the molecular and cognitive phenotypes associated with the pathogenic P301L tau mutation (rT2 mice) in relation to a genetically matched transgenic mouse overexpressing nonmutant (NM) 4-repeat (4R) human tau (rT1 mice). Both male and female mice were included in this study. Unexpectedly, we found that 4R NM human tau (hTau) exhibited abnormal dynamics in young mice that were lost with the P301L mutation, including elevated protein stability and hyperphosphorylation, which were associated with cognitive impairment in 5-month-old rT1 mice. Hyperphosphorylation of NM hTau was observed as early as 4 weeks of age, and transgene suppression for the first 4 or 12 weeks of life prevented abnormal molecular and cognitive phenotypes in rT1, demonstrating that NM hTau pathogenicity is specific to postnatal development. We also show that NM hTau exhibits stronger binding to microtubules than P301L hTau, and is associated with mitochondrial abnormalities. Overall, our genetically matched mice have revealed that 4R NM hTau overexpression is pathogenic in a manner distinct from classical aging-related tauopathy, underlining the importance of assaying the effects of transgenic disease-related proteins at appropriate stages in life. SIGNIFICANCE STATEMENT Due to differences in creation of transgenic lines, the pathological properties of the P301L mutation confers to the tau protein in vivo have remained elusive, perhaps contributing to the lack of disease-modifying therapies for tauopathies. In an attempt to characterize P301L-specific effects on tau biology and cognition in novel genetically matched transgenic mouse models, we surprisingly found that nonmutant human tau has development-specific pathogenic properties of its own. Our findings indicate that overexpression of 4-repeat human tau during postnatal development is associated with excessive microtubule binding, which may disrupt important cellular processes, such as mitochondrial dynamics, leading to elevated stability and hyperphosphorylation of tau, and eventual cognitive impairments.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1256-19.2019
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2020
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Involvement of β-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 19 ( 2007-05-08), p. 8167-8172
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 19 ( 2007-05-08), p. 8167-8172
    Abstract: The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid-β protein (Aβ), which forms amyloid plaques in Alzheimer's disease (AD), secreted APPα (sAPPα) which enhances memory, and the APP intracellular domain (AICD), which has been implicated in the regulation of gene transcription and calcium signaling. The β-site APP cleaving enzyme 1 (BACE1) cleaves APP in an activity-dependent manner to form Aβ, AICD, and secreted APPβ. Because this neural activity was shown to diminish synaptic transmission in vitro [Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) Neuron 37:925–937], the prevailing notion has been that this pathway diminishes synaptic function. Here we investigated the role of this pathway in vivo . We studied transgenic mice overproducing APP that do not develop AD pathology or memory deficits but instead exhibit enhanced spatial memory. We showed enhanced synaptic plasticity in the hippocampus that depends on prior synaptic activity. We found that the enhanced memory and synaptic plasticity are abolished by the ablation of one or both copies of the BACE1 gene, leading to a significant decrease in AICD but not of any other APP cleavage products. In contrast to the previously described negative effect of BACE1-mediated cleavage of APP on synaptic function in vitro , our in vivo work indicates that BACE1-mediated cleavage of APP can facilitate learning, memory, and synaptic plasticity.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0609521104
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Plaque-associated α-synuclein (NACP) pathology in aged transgenic mice expressing amyloid precursor protein
    Elsevier BV ; 2000
    In:  Brain Research Vol. 853, No. 2 ( 2000-01), p. 381-383
    Details
    In: Brain Research, Elsevier BV, Vol. 853, No. 2 ( 2000-01), p. 381-383
    Type of Medium: Online Resource
    ISSN: 0006-8993
    URL: Article
    DOI: 10.1016/S0006-8993(99)02207-6
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2000
    detail.hit.zdb_id: 1462674-3
    SSG: 12
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