title: Glucose deprivation increases tau phosphorylation via P38 mitogen-activated protein kinase.
abstract: Alterations of glucose metabolism have been observed in Alzheimer's disease (AD) brain. Previous studies showed that glucose deprivation increases amyloidogenesis via a BACE-1-dependent mechanism. However, no data are available on the effect that this condition may have on tau phosphorylation. In this study, we exposed neuronal cells to a glucose-free medium and investigated the effect on tau phosphorylation. Compared with controls, cells incubated in the absence of glucose had a significant increase in tau phosphorylation at epitopes Ser202/Thr205 and Ser404, which was associated with a selective activation of the P38 mitogen-activated protein kinase. Pharmacological inhibition of this kinase prevented the increase in tau phosphorylation, while fluorescence studies revealed its co-localization with phosphorylated tau. The activation of P38 was secondary to the action of the apoptosis signal-regulating kinase 1, as its down-regulation prevented it. Finally, glucose deprivation induced cell apoptosis, which was associated with a significant increase in both caspase 3 and caspase 12 active forms. Taken together, our studies reveal a new mechanism whereby glucose deprivation can modulate AD pathogenesis by influencing tau phosphorylation and suggest that this pathway may be a new therapeutic target for AD.
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Lauretti
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D017209:Apoptosis / Q000502:physiology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D053454:Caspase 12 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D016875:tau Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D053829:Amyloid Precursor Protein Secretases; C506444:CASP12 protein, human; D053454:Caspase 12; D053148:Caspase 3; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D005947:Glucose
keywords: Alzheimer's disease; amyloid beta; glucose deprivation; mitogen-activated protein kinase; neuronal cells; tau phosphorylation