Down-regulation of the ATP-binding cassette transporter 2 (Abca2) reduces amyloid-β production by altering nicastrin maturation and intracellular localization
| Autor: | Francesc X. Guix, Danyelle M. Townsend, Sebastian Munck, Colin Dingwall, Bart De Strooper, Krist'l Vennekens, Kenneth D. Tew, John B. Davis, Tina Wahle, Fabian Feiguin, Vasiliki Michaki, Carlos G. Dotti |
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| Přispěvatelé: | Research Foundation - Flanders, Belgian Science Policy Office, Foundation for Alzheimer Research, Gouvernement fédéral belge, Ministerio de Ciencia e Innovación (España) |
| Rok vydání: | 2012 |
| Předmět: |
Nicastrin
Down-Regulation Nerve Tissue Proteins ABCA2 Biochemistry Amyloid beta-Protein Precursor Mice Neurobiology Alzheimer Disease polycyclic compounds Amyloid precursor protein Animals Drosophila Proteins Humans APH-1 Molecular Biology Membrane Glycoproteins biology HEK 293 cells Cell Biology Subcellular localization Rats Drosophila melanogaster HEK293 Cells biology.protein lipids (amino acids peptides and proteins) ATP-Binding Cassette Transporters Amyloid Precursor Protein Secretases Amyloid precursor protein secretase Intracellular |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Clinical, pharmacological, biochemical, and genetic evidence support the notion that alteration of cholesterol homeostasis strongly predisposes to Alzheimer disease (AD). The ATP-binding cassette transporter-2 (Abca2), which plays a role in intracellular sterol trafficking, has been genetically linked to AD. It is unclear how these two processes are related. Here we demonstrate that down-regulation of Abca2 in mammalian cells leads to decreased amyloid-β (Aβ) generation. In vitro studies revealed altered γ-secretase complex formation in Abca2 knock-out cells due to the altered levels, post-translational modification, and subcellular localization of Nicastrin. Reduced Abca2 levels in mammalian cells in vitro, inDrosophila melanogaster and in mice resulted in altered γ-secretase processing of APP, and thus Aβ generation, without affecting Notch cleavage. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Fund for Scientific Research Flanders (FWO); Federal Office for Scientific Affairs (IUAP P6/43/); Stichting voor Alzheimer Onderzooek/Fondation pour la Recherche sur Maladie d’ Alzheimer (SAO/FRMA), the Flemish Government (Methusalem grant); Spanish Government Grants Ministerio de Ciencia e Innovación (Ingenio Consolider CSD2010-00064); Ministerio de Ciencia e Innovación (SAF2010-14906) |
| Databáze: | OpenAIRE |
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