title: Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: A new paradigm.
abstract: Clinical studies suggest a link between peripheral insulin resistance and cognitive dysfunction. Interestingly, post-mortem analyses of Alzheimer disease (AD) subjects demonstrated insulin resistance in the brain proposing a role for cognitive deficits observed in AD. However, the mechanisms responsible for the onset of brain insulin resistance (BIR) need further elucidations. Biliverdin reductase-A (BVR-A) emerged as a unique Ser/Thr/Tyr kinase directly involved in the insulin signaling and represents an up-stream regulator of the insulin signaling cascade. Because we previously demonstrated the oxidative stress (OS)-induced impairment of BVR-A in human AD brain, we hypothesize that BVR-A dysregulation could be associated with the onset of BIR in AD. In the present work, we longitudinally analyze the age-dependent changes of (i) BVR-A protein levels and activation, (ii) total oxidative stress markers levels (PC, HNE, 3-NT) as well as (iii) IR/IRS1 levels and activation in the hippocampus of the triple transgenic model of AD (3xTg-AD) mice. Furthermore, ad hoc experiments have been performed in SH-SY5Y neuroblastoma cells to clarify the molecular mechanism(s) underlying changes observed in mice. Our results show that OS-induced impairment of BVR-A kinase activity is an early event, which starts prior the accumulation of Aβ and tau pathology or the elevation of TNF-α, and that greatly contribute to the onset of BIR along the progression of AD pathology in 3xTg-Ad mice. Based on these evidence we, therefore, propose a new paradigm for which: OS-induced impairment of BVR-A is firstly responsible for a sustained activation of IRS1, which then causes the stimulation of negative feedback mechanisms (i.e. mTOR) aimed to turn-off IRS1 hyper-activity and thus BIR. Similar alterations characterize also the normal aging process in mice, positing BVR-A impairment as a possible bridge in the transition from normal aging to AD.
authors.affiliation: Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy; Universidad Autónoma de Chile, Instituto de Ciencias Biomédicas, Facultad de Salud, Avenida Pedro de Valdivia 425, Providencia, Santiago, Chile.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Barone
authors.affiliation: Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Domenico
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Via Napoli 20, 71122 Foggia, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cassano
authors.affiliation: Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Arena
authors.affiliation: Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Tramutola
authors.affiliation: Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Roma, Piazzale A. Moro 5, 00185 Roma, Italy.
authors.forename: Michele Angelo
authors.initials: MA
authors.lastname: Lavecchia
authors.affiliation: Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Coccia
authors.affiliation: Department of Chemistry, Markey Cancer Center, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA. Electronic address: dabcns@uky.edu.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.affiliation: Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy. Electronic address: marzia.perluigi@uniroma1.it.
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000201:enzymology*; D000818:Animals; D045744:Cell Line, Tumor; D006624:Hippocampus / Q000201:enzymology*; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D058570:TOR Serine-Threonine Kinases
keywords: 3xTg-AD mice; Alzheimer disease; Biliverdin reductase-A; Insulin resistance; Oxidative stress