title: Glucose deficit triggers tau pathology and synaptic dysfunction in a tauopathy mouse model.
abstract: Clinical investigations have highlighted a biological link between reduced brain glucose metabolism and Alzheimer's disease (AD). Previous studies showed that glucose deprivation may influence amyloid beta formation in vivo but no data are available on the effect that this condition might have on tau protein metabolism. In the current paper, we investigated the effect of glucose deficit on tau phosphorylation, memory and learning, and synaptic function in a transgenic mouse model of tauopathy, the h-tau mice. Compared with controls, h-tau mice with brain glucose deficit showed significant memory impairments, reduction of synaptic long-term potentiation, increased tau phosphorylation, which was mediated by the activation of P38 MAPK Kinase pathway. We believe our studies demonstrate for the first time that reduced glucose availability in the central nervous system directly triggers behavioral deficits by promoting the development of tau neuropathology and synaptic dysfunction. Since restoring brain glucose levels and metabolism could afford the opportunity to positively influence the entire AD phenotype, this approach should be considered as a novel and viable therapy for preventing and/or halting the disease progression.
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lauretti
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
authors.forename: J-G
authors.initials: JG
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Di Meco
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000544:Alzheimer Disease; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000503:physiopathology; D003847:Deoxyglucose; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D007858:Learning / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons; D010766:Phosphorylation; D011897:Random Allocation; D013569:Synapses / Q000378:metabolism / Q000502:physiology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; D003847:Deoxyglucose; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose