Improvement of BVR-A Activity Ameliorates Brain Insulin Resistance in Alzheimer Disease Following Intranasal Insulin Administration

Brain insulin resistance (b.i.r.) was proposed as a mechanistic mediator of the cognitive deficits observed in Alzheimer disease (AD). Interestingly, the efficacy of intranasal insulin (I-Ins) administration – which allows to directly transport insulin to the CNS – was proposed as an innovative therapeutic strategy to alleviate cognitive dysfunction in AD. However, significant gaps in our knowledge about the mechanisms underlying these beneficial outcomes still exist. We previously reported about the oxidative-stress (OS) induced impairment of biliverdin reductase A (BVR-A) [a novel direct target of the insulin receptor (IR) kinase activity] as an early event contributing to b.i.r. in AD. Indeed, under normal conditions, once IR-activated BVR-A controls the activation of the insulin receptor substrate (IRS)-1, thus representing an upstream regulator of the insulin signaling cascade. Conversely, along the progression of AD pathology, the OS-induced inactivation of BVR-A promotes the hyper-activation of the IR/IRS-1 axis, which finally lead to b.i.r.. Here we hypothesized that the I-Ins-associated beneficial effects on cognition would be mediated by the restoration of BVR-A activity. To this aim, we evaluated in vivo (i) changes of the insulin signaling cascade (ii) variations of total OS markers (PC, HNE, 3-NT), (iii) changes of AD neuropathology markers e.g., Aβ and tau levels, in the hippocampus of 3xTg-AD and WT mice undergoing an early (4 months) or late (10 moths) intranasal insulin treatment (1 U/day, 3 times per week, for 2 months). Furthermore, changes of cognitive functions assessed through the morris water maze (MWM) and the novel object recognition (NOR) tasks, were evaluated. We found that I-Ins administration rescue the activation of BVR-A both in young and old 3xTg-AD mice. Improved BVR-A activity is associated with (i) reduced OS markers, (ii) a restoration of the insulin signaling cascade and (iii) a reduction of Tau pathology in the hippocampus. All these changes parallel an improved cognition. Interestingly, cell-based experiments confirmed the role of BVR-A by showing no beneficial effects of insulin when BVR-A is knocked-down.