Activation of PKR causes amyloid ß-peptide accumulation via De-Repression of Bace1 expression
ILL-Raga, G. (Universitat Pompeu Fabra)
Palomer, E. (Universitat Pompeu Fabra)
Wozniak, M.A. (University of Manchester)
Ramos-Fernández, E. (Universitat Pompeu Fabra)
Bosch-Morató, M. (Universitat Pompeu Fabra)
Tajes, Marta (Universitat Pompeu Fabra)
Guix, F.X. (Universitat Pompeu Fabra)
Galán, J.J. (NeoCodex)
Clarimón, Jordi (Institut d'Investigació Biomèdica Sant Pau)
Antúnez, Carmen (Hospital Universitario Virgen de la Arrixaca (Múrcia))
Real, L.M. (NeoCodex)
Boada, Mercè (Hospital Universitari Vall d'Hebron)
Itzhaki, R.F. (University of Manchester)
Fandos, C. (Universitat Pompeu Fabra)
Muñoz, F. J. (Universitat Pompeu Fabra)
Universitat Autònoma de Barcelona

Date:	2011
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 AD. © 2011 ILL-Raga et al.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	PloS one, Vol. 6 Núm. 6 (2011) , p. e21456, ISSN 1932-6203

DOI: 10.1371/journal.pone.0021456
PMID: 21738672

10 p, 568.2 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles