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

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 kappa B (NF-kappa B) 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-kappa B activation and production of tumor necrosis factor alpha (TNF alpha) and interleukin (IL)-1 beta at 12 months of age without decrease of A beta 42 levels and memory deficits. Surprisingly, PKR inhibition failed to prevent IL-1 beta-mediated inflammation and induced a great increase in beta-amyloid peptide (A beta 42) levels at 18 months of age. In this model, our findings highlight the lack of relationship between inflammation and A beta 42 levels. Moreover, the age-dependent inflammatory response must be carefully taken into account in the establishment of an anti-inflammatory therapy in AD.