title: PKR downregulation prevents neurodegeneration and β-amyloid production in a thiamine-deficient model.
abstract: Brain thiamine homeostasis has an important role in energy metabolism and displays reduced activity in Alzheimer's disease (AD). Thiamine deficiency (TD) induces regionally specific neuronal death in the animal and human brains associated with a mild chronic impairment of oxidative metabolism. These features make the TD model amenable to investigate the cellular mechanisms of neurodegeneration. Once activated by various cellular stresses, including oxidative stress, PKR acts as a pro-apoptotic kinase and negatively controls the protein translation leading to an increase of BACE1 translation. In this study, we used a mouse TD model to assess the involvement of PKR in neuronal death and the molecular mechanisms of AD. Our results showed that the TD model activates the PKR-eIF2α pathway, increases the BACE1 expression levels of Aβ in specific thalamus nuclei and induces motor deficits and neurodegeneration. These effects are reversed by PKR downregulation (using a specific inhibitor or in PKR knockout mice).
authors.affiliation: 1] Inserm UMR-S942, Paris 75010, France [2] Department of Histology, Pathology and Biochemistry, Saint Louis Lariboisière Fernand Hospital, Service AP-HP, University of Paris Diderot, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Mouton-Liger
authors.affiliation: Inserm UMR-S942, Paris 75010, France.
authors.forename: A-S
authors.initials: AS
authors.lastname: Rebillat
authors.affiliation: 1] Inserm UMR-S942, Paris 75010, France [2] Department of Histology, Pathology and Biochemistry, Saint Louis Lariboisière Fernand Hospital, Service AP-HP, University of Paris Diderot, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Gourmaud
authors.affiliation: 1] Inserm UMR-S942, Paris 75010, France [2] Department of Histology, Pathology and Biochemistry, Saint Louis Lariboisière Fernand Hospital, Service AP-HP, University of Paris Diderot, Paris, France [3] Clinical and Research Memory Center, Paris Nord Ile de France Saint Louis Lariboisière Fernand Hospital, AP-HP, University of Paris Diderot, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Paquet
authors.affiliation: Inserm UMR-S942, Paris 75010, France.
authors.forename: A
authors.initials: A
authors.lastname: Leguen
authors.affiliation: 1] Department of Histology, Pathology and Biochemistry, Saint Louis Lariboisière Fernand Hospital, Service AP-HP, University of Paris Diderot, Paris, France [2] Clinical and Research Memory Center, Paris Nord Ile de France Saint Louis Lariboisière Fernand Hospital, AP-HP, University of Paris Diderot, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Dumurgier
authors.affiliation: Sanofi-Aventis Therapeutic Strategy Unit Aging, Chilly-Mazarin, France.
authors.forename: P
authors.initials: P
authors.lastname: Bernadelli
authors.affiliation: Sanofi-Aventis Therapeutic Strategy Unit Aging, Chilly-Mazarin, France.
authors.forename: V
authors.initials: V
authors.lastname: Taupin
authors.affiliation: Sanofi-Aventis Therapeutic Strategy Unit Aging, Chilly-Mazarin, France.
authors.forename: L
authors.initials: L
authors.lastname: Pradier
authors.affiliation: Sanofi-Aventis Therapeutic Strategy Unit Aging, Chilly-Mazarin, France.
authors.forename: T
authors.initials: T
authors.lastname: Rooney
authors.affiliation: 1] Inserm UMR-S942, Paris 75010, France [2] Department of Histology, Pathology and Biochemistry, Saint Louis Lariboisière Fernand Hospital, Service AP-HP, University of Paris Diderot, Paris, France [3] Clinical and Research Memory Center, Paris Nord Ile de France Saint Louis Lariboisière Fernand Hospital, AP-HP, University of Paris Diderot, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Hugon
mesh_terms: D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D021381:Protein Transport; D015398:Signal Transduction; D013831:Thiamine / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D015852:Eukaryotic Initiation Factor-2; D019892:eIF-2 Kinase; D053148:Caspase 3; D013831:Thiamine