Biliverdin Reductase-A Mediates the Beneficial Effects of Intranasal Insulin in Alzheimer Disease

Abstract

Impairment of biliverdin reductase-A (BVR-A) is an early event leading to brain insulin resistance in AD. Intranasal insulin (INI) administration is under evaluation as a strategy to alleviate brain insulin resistance; however, the molecular mechanisms underlying INI beneficial effects are still unclear. We show that INI improves insulin signaling activation in the hippocampus and cortex of adult and aged 3×Tg-AD mice by ameliorating BVR-A activation. These changes were associated with a reduction of nitrosative stress, Tau phosphorylation, and Aβ oligomers in brain, along with improved cognitive functions. The role of BVR-A was strengthened by showing that cells lacking BVR-A: (i) develop insulin resistance if treated with insulin and (ii) can be recovered from insulin resistance only if treated with a BVR-A-mimetic peptide. These novel findings shed light on the mechanisms underlying INI treatment effects and suggest BVR-A as potential therapeutic target to prevent brain insulin resistance in AD.

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

“…Thus, it is clear that BVRA can impact insulin signaling through its interactions with AKT. Others have shown that the loss of BVRA in the brain causes insulin-resistance that occurs in Alzheimer's disease [60][61][62]. However, the loss of BVRA in obesity can result in hyperactivation of insulin signaling [18].…”

Tat-Biliverdin Reductase A Exerts a Protective Role in Oxidative Stress-Induced Hippocampal Neuronal Cell Damage by Regulating the Apoptosis and MAPK Signaling

“…However, impairment of biliverdin reductase is a common clinical feature in the symptomatology of AD and type 2 diabetes mellitus (T2DM). These reports suggest that biliverdin reductase is important in the prevention of AD and T2DM [8,9,13]. Even though biliverdin reductase is involved in various diseases, the role of this enzyme in ischemic insults has not been investigated yet.…”

“…Biliverdin reductase and bilirubin are involved in various diseases, including brain damage and protection against oxidative stress-induced neuronal injury [6][7][8][9]. BLVRA has an antioxidant function on ROS via production of bilirubin.…”

Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory

“…Hippocampal subfields and electrode positions were identified with the aid of 4ϫ and 40ϫ water-immersion objectives on an upright microscope equipped with differential interference contrast optics under infrared illumination (BX51WI; Olympus) and video observation (BTE-B050-U CMOS camera; Mightex). Neighboring pairs of pyramidal cells were recorded simultaneously in CA1 by single stimulating bipolar tungsten electrode (FHC) placed on the Schaffer collateral fibers, as described previously (Barone et al, 2019). Slices were incubated in artificial CSF (ACSF) containing the following (in mM): 119 NaCl, 2.5 KCl, 4 CaCl 2 , 4 MgCl 2 , 1 NaH 2 PO 4 , 26 NaHCO 3 , 11 D-glucose, and 0.005 2-chloroadenosine, gassed with 95% O 2 /5% CO 2 .…”