Impairment of biliverdin reductase-A promotes brain insulin resistance in Alzheimer disease: A new paradigm

Eugenio Barone, Fabio Di Domenico, Tommaso Cassano, Andrea Arena, Antonella Tramutola, Michele Angelo Lavecchia, Raffaella Coccia, D. Allan Butterfield, Marzia Perluigi

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

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.

Original languageEnglish
Pages (from-to)127-142
Number of pages16
JournalFree Radical Biology and Medicine
Volume91
DOIs
StatePublished - Feb 1 2016

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.

Keywords

  • 3xTg-AD mice
  • Alzheimer disease
  • Biliverdin reductase-A
  • Insulin resistance
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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