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

Free Radic Biol Med. 2016 Feb;91:127-42. doi: 10.1016/j.freeradbiomed.2015.12.012. Epub 2015 Dec 15.

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.

Keywords: 3xTg-AD mice; Alzheimer disease; Biliverdin reductase-A; Insulin resistance; Oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Alzheimer Disease / enzymology*
  • Animals
  • Cell Line, Tumor
  • Hippocampus / enzymology*
  • Humans
  • Insulin Resistance*
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oxidative Stress
  • Oxidoreductases Acting on CH-CH Group Donors / genetics
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism*
  • Protein Processing, Post-Translational
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Tumor Necrosis Factor-alpha
  • Oxidoreductases Acting on CH-CH Group Donors
  • biliverdin reductase
  • TOR Serine-Threonine Kinases