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  • 1
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    Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles (2001)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2001-06-16
    Description: The microtubule-binding protein tau has been implicated in the pathogenesis of Alzheimer's disease and related disorders. However, the mechanisms underlying tau-mediated neurotoxicity remain unclear. We created a genetic model of tau-related neurodegenerative disease by expressing wild-type and mutant forms of human tau in the fruit fly Drosophila melanogaster. Transgenic flies showed key features of the human disorders: adult onset, progressive neurodegeneration, early death, enhanced toxicity of mutant tau, accumulation of abnormal tau, and relative anatomic selectivity. However, neurodegeneration occurred without the neurofibrillary tangle formation that is seen in human disease and some rodent tauopathy models. This fly model may allow a genetic analysis of the cellular mechanisms underlying tau neurotoxicity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wittmann, C W -- Wszolek, M F -- Shulman, J M -- Salvaterra, P M -- Lewis, J -- Hutton, M -- Feany, M B -- New York, N.Y. -- Science. 2001 Jul 27;293(5530):711-4. Epub 2001 Jun 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Room 514, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11408621" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylcholine/metabolism ; Aging ; Animals ; Animals, Genetically Modified ; Brain/pathology/ultrastructure ; *Disease Models, Animal ; *Drosophila melanogaster/genetics ; Humans ; Mutation ; Nerve Degeneration ; Nerve Endings/metabolism/ultrastructure ; Neurodegenerative Diseases/metabolism/*pathology ; Neurofibrillary Tangles/ultrastructure ; Neurons/metabolism/*ultrastructure ; Neuropil/ultrastructure ; Phosphorylation ; Vacuoles/ultrastructure ; tau Proteins/chemistry/genetics/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Functional links between Abeta toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-10-29
    Description: Abeta (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Abeta toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Abeta was previously unknown. The factors identified in yeast modified Abeta toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Abeta impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Abeta, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281757/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281757/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Treusch, Sebastian -- Hamamichi, Shusei -- Goodman, Jessica L -- Matlack, Kent E S -- Chung, Chee Yeun -- Baru, Valeriya -- Shulman, Joshua M -- Parrado, Antonio -- Bevis, Brooke J -- Valastyan, Julie S -- Han, Haesun -- Lindhagen-Persson, Malin -- Reiman, Eric M -- Evans, Denis A -- Bennett, David A -- Olofsson, Anders -- DeJager, Philip L -- Tanzi, Rudolph E -- Caldwell, Kim A -- Caldwell, Guy A -- Lindquist, Susan -- F32 NS067782-02/NS/NINDS NIH HHS/ -- K08 AG034290/AG/NIA NIH HHS/ -- K08AG034290/AG/NIA NIH HHS/ -- P30 AG019610/AG/NIA NIH HHS/ -- P30AG10161/AG/NIA NIH HHS/ -- R01 AG015819/AG/NIA NIH HHS/ -- R01 AG017917/AG/NIA NIH HHS/ -- R01AG15819/AG/NIA NIH HHS/ -- R01AG17917/AG/NIA NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Dec 2;334(6060):1241-5. doi: 10.1126/science.1213210. Epub 2011 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22033521" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/*genetics/*metabolism ; Amyloid beta-Peptides/chemistry/genetics/*metabolism ; Animals ; Animals, Genetically Modified ; Caenorhabditis elegans/cytology/genetics/metabolism ; Cell Membrane/metabolism ; Cells, Cultured ; Clathrin/metabolism ; Cytoskeleton/metabolism ; Disease Susceptibility ; *Endocytosis ; Genetic Association Studies ; Genetic Testing ; Glutamates/metabolism ; Humans ; Monomeric Clathrin Assembly Proteins/genetics/metabolism ; Neurons/physiology ; Peptide Fragments/chemistry/genetics/*metabolism ; Protein Multimerization ; Protein Transport ; Rats ; Risk Factors ; *Saccharomyces cerevisiae/cytology/genetics/growth & development/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Secretory Pathway
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    A coding variant in CR1 interacts with APOE-{varepsilon}4 to influence cognitive decline (2012)
    Oxford University Press
    Details
    Publication Date: 2012-04-25
    Description: Complement receptor 1 ( CR1 ) is an Alzheimer's disease (AD) susceptibility locus that also influences AD-related traits such as episodic memory decline and neuritic amyloid plaque deposition. We implemented a functional fine-mapping approach, leveraging intermediate phenotypes to identify functional variant(s) within the CR1 locus. Using 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project, we tested 41 single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium block containing the published CR1 AD SNP (rs6656401) for associations with episodic memory decline, and then examined the functional consequences of the top result. We report that a coding variant in the LHR-D (long homologous repeat D) region of the CR1 gene, rs4844609 (Ser1610Thr, minor allele frequency = 0.02), is associated with episodic memory decline and accounts for the known effect of the index SNP rs6656401 ( D ' = 1, r 2 = 0.084) on this trait. Further, we demonstrate that the coding variant's effect is largely dependent on an interaction with APOE-4 and mediated by an increased burden of AD-related neuropathology. Finally, in our data, this coding variant is also associated with AD susceptibility (joint odds ratio = 1.4). Taken together, our analyses identify a CR1 coding variant that influences episodic memory decline; it is a variant known to alter the conformation of CR1 and points to LHR-D as the functional domain within the CR1 protein that mediates the effect on memory decline. We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variant's effect and suggest that CR1 may be an important intermediate in the clearance of Aβ42 particles by C1q.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms (2014)
    Oxford University Press
    Details
    Publication Date: 2014-01-24
    Description: Using a Drosophila model of Alzheimer's disease (AD), we systematically evaluated 67 candidate genes based on AD-associated genomic loci ( P 〈 10 –4 ) from published human genome-wide association studies (GWAS). Genetic manipulation of 87 homologous fly genes was tested for modulation of neurotoxicity caused by human Tau, which forms neurofibrillary tangle pathology in AD. RNA interference (RNAi) targeting 9 genes enhanced Tau neurotoxicity, and in most cases reciprocal activation of gene expression suppressed Tau toxicity. Our screen implicates cindr , the fly ortholog of the human CD2AP AD susceptibility gene, as a modulator of Tau-mediated disease mechanisms. Importantly, we also identify the fly orthologs of FERMT2 and CELF1 as Tau modifiers, and these loci have been independently validated as AD susceptibility loci in the latest GWAS meta-analysis. Both CD2AP and FERMT2 have been previously implicated with roles in cell adhesion, and our screen additionally identifies a fly homolog of the human integrin adhesion receptors, ITGAM and ITGA9 , as a modifier of Tau neurotoxicity. Our results highlight cell adhesion pathways as important in Tau toxicity and AD susceptibility and demonstrate the power of model organism genetic screens for the functional follow-up of human GWAS.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 5
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    Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms (2013)
    Oxford University Press
    Details
    Publication Date: 2013-09-25
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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