Activation of PKR causes amyloid beta-peptide accumulation via De-Repression of Bace1 expression

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• dc.contributor.author Ill-Raga, Gerard, 1982-ca
• dc.contributor.author Palomer, Ernestca
• dc.contributor.author Wozniak, Matthew Aca
• dc.contributor.author Ramos Fernández, Eva, 1984-ca
• dc.contributor.author Bosch Morató, Mònica, 1986-ca
• dc.contributor.author Tajes Orduña, Martaca
• dc.contributor.author Guix Ràfols, Francesc Xavierca
• dc.contributor.author Galán, José Jca
• dc.contributor.author Clarimón Echevarría, Jordica
• dc.contributor.author Antúnez, Carmenca
• dc.contributor.author Real, Luis Mca
• dc.contributor.author Boada, Mercèca
• dc.contributor.author Itzhaki, Ruth Fca
• dc.contributor.author Fandos, Césarca
• dc.contributor.author Muñoz López, Francisco José, 1964-ca
• dc.date.accessioned 2015-05-04T08:56:20Z
• dc.date.available 2015-05-04T08:56:20Z
• dc.date.issued 2011ca
• dc.description.abstract BACE1 is a key enzyme involved in the production of amyloid ß-peptide (Aß) in Alzheimer's disease (AD) brains. Normally, its expression is constitutively inhibited due to the presence of the 5′untranslated region (5′UTR) in the BACE1 promoter. BACE1 expression is activated by phosphorylation of the eukaryotic initiation factor (eIF)2-alpha, which reverses the inhibitory effect exerted by BACE1 5′UTR. There are four kinases associated with different types of stress that could phosphorylate eIF2-alpha. Here we focus on the double-stranded (ds) RNA-activated protein kinase (PKR). PKR is activated during viral infection, including that of herpes simplex virus type 1 (HSV1), a virus suggested to be implicated in the development of AD, acting when present in brains of carriers of the type 4 allele of the apolipoprotein E gene. HSV1 is a dsDNA virus but it has genes on both strands of the genome, and from these genes complementary RNA molecules are transcribed. These could activate BACE1 expression by the PKR pathway. Here we demonstrate in HSV1-infected neuroblastoma cells, and in peripheral nervous tissue from HSV1-infected mice, that HSV1 activates PKR. Cloning BACE1 5′UTR upstream of a luciferase (luc) gene confirmed its inhibitory effect, which can be prevented by salubrinal, an inhibitor of the eIF2-alpha phosphatase PP1c. Treatment with the dsRNA analog poly (I:C) mimicked the stimulatory effect exerted by salubrinal over BACE1 translation in the 5′UTR-luc construct and increased Aß production in HEK-APPsw cells. Summarizing, our data suggest that PKR activated in brain by HSV1 could play an important role in the development of ADca
• dc.description.sponsorship Neocodex is a private research organization (more than 70 articles in indexes of international research journals in the last 8 years). Neocodex’s work on this project was design, implementation, analysis and interpretation of genetic studies of the PKR gene that is included in this manuscript. Neocodex also coordinates the construction of the DNA bank employed in this draft. The work was carried out with funds from this entity and a project funded by the Alzheimur Foundation. The other funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This w ork was also supported by the Spanish Ministerio de Ciencia y Tecnología (FIS: PI07/0593; Red HERACLES RD06/0009/002)en
• dc.format.mimetype application/pdfca
• dc.identifier.citation Ill-Raga G, Palomer E, Wozniak MA, Ramos-Fernández E, Bosch-Morató M, Tajes M et al. Activation of PKR causes amyloid beta-peptide accumulation via De-Repression of Bace1 expression. PLoS ONE. 2011; 6(6): e21456. DOI 10.1371/journal.pone.0021456ca
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0021456
• dc.identifier.issn 1932-6203ca
• dc.identifier.uri http://hdl.handle.net/10230/23512
• dc.language.iso engca
• dc.publisher Public Library of Science (PLoS)ca
• dc.relation.ispartof PLoS ONE. 2011; 6(6): e21456
• dc.rights © 2011 ILL-Raga et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.other Proteïna beta-amiloideca
• dc.subject.other Cultius cel·lularsca
• dc.title Activation of PKR causes amyloid beta-peptide accumulation via De-Repression of Bace1 expressionen
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca