title: Activation of PKR causes amyloid ß-peptide accumulation via de-repression of BACE1 expression.
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.
authors: Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.
authors: Gerard
authors: G
authors: Ill-Raga
authors: Ernest
authors: E
authors: Palomer
authors: Matthew A
authors: MA
authors: Wozniak
authors: Eva
authors: E
authors: Ramos-Fernández
authors: Mònica
authors: M
authors: Bosch-Morató
authors: Marta
authors: M
authors: Tajes
authors: Francesc X
authors: FX
authors: Guix
authors: José J
authors: JJ
authors: Galán
authors: Jordi
authors: J
authors: Clarimón
authors: Carmen
authors: C
authors: Antúnez
authors: Luis M
authors: LM
authors: Real
authors: Mercé
authors: M
authors: Boada
authors: Ruth F
authors: RF
authors: Itzhaki
authors: César
authors: C
authors: Fandos
authors: Francisco J
authors: FJ
authors: Muñoz
mesh_terms: D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019892:eIF-2 Kinase; D053829:Amyloid Precursor Protein Secretases