title: Modulation of AD neuropathology and memory impairments by the isoprostane F2α is mediated by the thromboxane receptor.
abstract: Beside amyloid-β plaques and neurofibrillary tangles, brain oxidative damage has been constantly implicated in Alzheimer's disease (AD) pathogenesis. Numerous studies demonstrated that F2-isoprostanes, markers of in vivo lipid peroxidation, are elevated in AD patients and mouse models of the disease. Previously, we showed that the 8-isoprostaneF2α, (8ISO) increases brain amyloid-β levels and deposition in the Tg2576 mice. However, no data are available on its effects on behavior and tau metabolism. To this end, we characterize the behavioral, biochemical, and neuropathologic effects of 8ISO in the triple transgenic mouse model. Compared with controls, mice receiving 8ISO showed significant memory deficits, increase in tau phosphorylation, activation of the cyclin kinase 5 pathway, and neuroinflammation. All these effects were blocked by pharmacologic blockade of the thromboxane receptor. Our findings establish the novel functional role that oxidative stress via the formation of this isoprostane plays in the development of cognitive impairments and AD-related tau neuropathology. It provides important preclinical support to the neurobiological importance of the thromboxane receptor as an active player in the pathogenesis of AD.
authors.affiliation: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Lauretti
authors.affiliation: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Meco
authors.affiliation: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Chu
authors.affiliation: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA. Electronic address: praticod@temple.edu.
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001519:Behavior; D001921:Brain / Q000378:metabolism; D003071:Cognition; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D008568:Memory; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000235:genetics; D010766:Phosphorylation; D017482:Receptors, Thromboxane / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D017482:Receptors, Thromboxane; D016875:tau Proteins; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost
keywords: Alzheimer's disease; Amyloid beta; Isoprostanes; Lipid peroxidation; Oxidative stress; Tau; Transgenic mouse models