title: Neuroinflammation and Aβ accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder, marked by senile plaques composed of amyloid-β (Aβ) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have suggested that systemic inflammation could contribute to neuroinflammation and enhanced Aβ cerebral concentrations. The molecular pathways leading to these events are not fully understood. PKR is a pro-apoptotic kinase that can trigger inflammation and accumulates in the brain and cerebrospinal fluid of AD patients. The goal of the present study was to assess if LPS-induced neuroinflammation and Aβ production could be altered by genetic PKR down regulation. The results show that, in the hippocampus of LPS-injected wild type mice, neuroinflammation, cytokine release and Aβ production are significantly increased and not in LPS-treated PKR knock-out mice. In addition BACE1 and activated STAT3 levels, a putative transcriptional regulator of BACE1, were not found increased in the brain of PKR knock-out mice as observed in wild type mice. Using PET imaging, the decrease of hippocampal metabolism induced by systemic LPS was not observed in LPS-treated PKR knock-out mice. Altogether, these findings demonstrate that PKR plays a major role in brain changes induced by LPS and could be a valid target to modulate neuroinflammation and Aβ production.
authors: Inserm UMR-S942, Lariboisiere Hospital, Paris, France.
authors: Anne-Sophie
authors: AS
authors: Carret-Rebillat
authors: Inserm UMR-S942, Lariboisiere Hospital, Paris, France.
authors: Clarisse
authors: C
authors: Pace
authors: Inserm UMR-S942, Lariboisiere Hospital, Paris, France.
authors: Sarah
authors: S
authors: Gourmaud
authors: In vivo preclinical imaging facility, IFR 114 - University of Lille, Nord of France, CHU Lille, France.
authors: Laura
authors: L
authors: Ravasi
authors: Inserm UMR-S942, Lariboisiere Hospital, Paris, France.
authors: Samantha
authors: S
authors: Montagne-Stora
authors: Inserm UMR-S839 Institut du Fer a Moulin and Inserm UMR932, Paris, France.
authors: Sophie
authors: S
authors: Longueville
authors: Inserm UMR-S942, Lariboisiere Hospital, Paris, France.
authors: Marion
authors: M
authors: Tible
authors: Inserm UMR-S942, Lariboisiere Hospital, Paris, France.
authors: Erika
authors: E
authors: Sudol
authors: Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR.
authors: Raymond Chuen-Chung
authors: RC
authors: Chang
authors: 1] Inserm UMR-S942, Lariboisiere Hospital, Paris, France [2] Memory Center, and Department of Histology, Lariboisiere Hospital, University of Paris Diderot, AP-HP, Paris, France.
authors: Claire
authors: C
authors: Paquet
authors: Inserm UMR-S942, Lariboisiere Hospital, Paris, France.
authors: François
authors: F
authors: Mouton-Liger
authors: 1] Inserm UMR-S942, Lariboisiere Hospital, Paris, France [2] Memory Center, and Department of Histology, Lariboisiere Hospital, University of Paris Diderot, AP-HP, Paris, France.
authors: Jacques
authors: J
authors: Hugon
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D050796:STAT3 Transcription Factor / Q000378:metabolism; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; D019892:eIF-2 Kinase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse