Peripheral inflammation increases PKR, GSK3β, and tau phosphorylation in wild-type mice

Abstract

Systemic inflammation is correlated with dementia progression. Pro-inflammatory molecules can communicate from the periphery to the central nervous system to induce neuroinflammation and neurodegeneration. Our protein of interest is the pro-apoptotic kinase PKR (the double strand-RNA dependent protein kinase). Increased activated PKR levels were found in AD patients brain and cerebrospinal fluid. PKR activation can be triggered by inflammatory stresses and induces neurotoxicity in vitro. Is in vivo PKR-mediated inflammation involved in AD neurodegenerative process? C57BL/6 wild type mice were injected intraperitoneally with LPS (1mk/kg) versus saline once a day for 3 days to induce PKR activation and neuroinflammation (LPS is the bacilli gram negative endotoxin lipopolysaccharide). Brains were collected and dissected, immunohistochemistry and western blotting were performed for neuroinflammation, PKR activation and AD pathological hallmarks (as Tau hyperphosphorylation). Mice showed endotoxin-induced sickness behaviour including body weight loss and elevated serum cytokine levels (IL1β, IL6 and IL10). Microglial activation (Iba1 staining), neuronal apopotosis (cleaved caspase 3 staining) and 30% increase of PKR, GSK3β and Tau phosphorylation (in western blotting) were found in hippocampus and cortex of LPS-treated mice. PKR could be involved in the signalling of neurofibrillary tangles formation after a systemic inflammatory challenge.