title: Pharmacological inhibition of PKR in APPswePS1dE9 mice transiently prevents inflammation at 12 months of age but increases Aβ42 levels in the late stages of the Alzheimer's disease.
abstract: The double-stranded RNA-dependent protein kinase (PKR) is switched on by a wide range of stimuli, including the amyloid peptide. Then, PKR transmits signals to the translational machinery, apoptosis and inflammatory signaling pathways by interacting with some adapters. In virus-infected cells, PKR engages the nucleus factor κB (NF-κB) pathway. In many models of Alzheimer's disease (AD) and patients with AD, PKR was activated. Furthermore, there is strong evidence implicating the inflammatory process in the AD brain. However, the PKR involvement in inflammatory responses in AD is not elucidated. Based on our previous in vitro results, the aim of this study was to evaluate the effects of a pharmacological inhibition of PKR in inflammation in APPswePS1dE9 transgenic mice. Our results showed that PKR inhibition prevented the NF-κB activation and production of tumor necrosis factor alpha (TNFα) and interleukin (IL)-1β at 12 months of age without decrease of Aβ42 levels and memory deficits. Surprisingly, PKR inhibition failed to prevent IL-1β- mediated inflammation and induced a great increase in β-amyloid peptide (Aβ42) levels at 18 months of age. In this model, our findings highlight the lack of relationship between inflammation and Aβ42 levels. Moreover, the age-dependent inflammatory response must be carefully taken into account in the establishment of an anti-inflammatory therapy in AD.
authors.affiliation: Research Group on Brain Aging, GReViC EA 3808, 6 rue de la Milétrie BP 199, 86034 Poitiers Cedex, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Couturier
authors.forename: Marc
authors.initials: M
authors.lastname: Paccalin
authors.forename: Claire
authors.initials: C
authors.lastname: Lafay-Chebassier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ingrand
authors.forename: Jérémy
authors.initials: J
authors.lastname: Pinguet
authors.forename: Raymond
authors.initials: R
authors.lastname: Pontcharraud
authors.forename: Olivier
authors.initials: O
authors.lastname: Guillard
authors.forename: Bernard
authors.initials: B
authors.lastname: Fauconneau
authors.forename: Guylène
authors.initials: G
authors.lastname: Page
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D019892:eIF-2 Kinase