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

• Published in: Free radical biology & medicine Vol. 91; pp. 127 - 142
• Main Authors: Barone, Eugenio, Di Domenico, Fabio, Cassano, Tommaso, Arena, Andrea, Tramutola, Antonella, Lavecchia, Michele Angelo, Coccia, Raffaella, Butterfield, D. Allan, Perluigi, Marzia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2016
• Subjects: 3xTg-AD mice; Aging; Alzheimer disease; Alzheimer Disease - enzymology; Animals; Biliverdin reductase-A; 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; Oxidative stress; Insulin resistance; Alzheimer disease; 3xTg-AD mice; Biliverdin reductase-A
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2015.12.012

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. [Display omitted] •Reduced BVR-A levels and activation are an early event in the progression of AD.•Oxidative stress promotes BVR-A inactivation.•Persistent inactivation of BVR-A is associated with IRS1 inhibition.•BVR-A inactivation-associated IRS-1 inhibition is mediated by mTOR hyperactivation.•Insulin promotes IRS1 inhibition when BVR-A does not function properly.