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Verfasst von:Page, Richard M. [VerfasserIn]   i
 Horn, Thomas [VerfasserIn]   i
 Boutros, Michael [VerfasserIn]   i
Titel:Loss of PAFAH1B2 reduces amyloid-β generation by promoting the degradation of amyloid precursor protein C-terminal fragments
Verf.angabe:Richard M. Page, Anna Münch, Thomas Horn, Peer-Hendrik Kuhn, Alessio Colombo, Orly Reiner, Michael Boutros, Harald Steiner, Stefan F. Lichtenthaler, and Christian Haass
E-Jahr:2012
Jahr:Sept. 27, 2012
Umfang:11 S.
Fussnoten:Gesehen am 17.05.2018
Titel Quelle:Enthalten in: The journal of neuroscience
Ort Quelle:Washington, DC : Soc., 1981
Jahr Quelle:2012
Band/Heft Quelle:32(2012), 50, Seite 18204-18214
ISSN Quelle:1529-2401
Abstract:Amyloid-β peptide (Aβ) is believed to play a central role in the pathogenesis of Alzheimer9s disease. In view of the side effects associated with inhibiting the secretases that produce Aβ, new molecular targets are required to provide alternative therapeutic options. We used RNA interference (RNAi) to systematically screen the Drosophila genome to identify genes that modulate Aβ production upon knockdown. RNAi of 41 genes in Drosophila cells significantly lowered Aβ without affecting general secretion or viability. After the γ-secretase complex components, the most potent effect was observed for platelet activating factor acetylhydrolase α (Paf-AHα), and, in mammalian cells, the effect was replicated for its ortholog PAFAH1B2. Knockdown of PAFAH1B2 strongly reduced Aβ secretion from human cells, and this effect was confirmed in primary cells derived from PAFAH1B2 knock-out mice. Reduced Aβ production was not attributable to altered β-amyloid precursor protein (APP) ectodomain shedding but was a result of an enhanced degradation of APP C-terminal fragments (CTFs) in the absence of PAFAH1B2 but not its close homolog PAFAH1B3. Enhanced degradation of APP CTFs was selective because no such effects were obtained for Notch or E-/N-cadherin. Thus, we have identified an important protein that can selectively modify Aβ generation via a novel mechanism, namely enhanced degradation of its immediate precursor. In view of the absence of a neurological phenotype in PAFAH1B2 knock-out mice, targeted downregulation of PAFAH1B2 may be a promising new strategy for lowering Aβ.
DOI:doi:10.1523/JNEUROSCI.2681-12.2012
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext: http://dx.doi.org/10.1523/JNEUROSCI.2681-12.2012
 Volltext: http://www.jneurosci.org/content/32/50/18204
 DOI: https://doi.org/10.1523/JNEUROSCI.2681-12.2012
Datenträger:Online-Ressource
Sprache:eng
K10plus-PPN:1575269465
Verknüpfungen:→ Zeitschrift

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