Molecular Neurobiology

, Volume 56, Issue 4, pp 2922–2943 | Cite as

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

  • Eugenio Barone
  • Antonella Tramutola
  • Francesca Triani
  • Silvio Calcagnini
  • Fabio Di Domenico
  • Cristian Ripoli
  • Silvana Gaetani
  • Claudio Grassi
  • D Allan Butterfield
  • Tommaso CassanoEmail author
  • Marzia PerluigiEmail author


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.


Alzheimer disease Biliverdin reductase-A Insulin resistance Intranasal Neuroprotection 


Author Contribution

EB, TC, and MP designed the study. EB, AT, FT, SC, and FDD performed the mouse experiments. TC and SG performed the behavioral tests. CR performed the electrophysiology experiments. EB, TC, MP, CG, and DAB analyzed and interpreted the data. EB and MP drafted the manuscript. All authors revised the manuscript critically for important intellectual content and approved the final version.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1231_MOESM1_ESM.docx (138.4 mb)
ESM 1 (DOCX 141686 kb)


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Authors and Affiliations

  1. 1.Department of Biochemical Sciences “A. Rossi-Fanelli”Sapienza University of RomeRomeItaly
  2. 2.Instituto de Ciencias Biomédicas, Facultad de SaludUniversidad Autónoma de ChileSantiagoChile
  3. 3.Department of Physiology and Pharmacology “V. Erspamer”Sapienza University of RomeRomeItaly
  4. 4.Institute of Human PhysiologyUniversità Cattolica del Sacro CuoreRomeItaly
  5. 5.Fondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
  6. 6.Department of Chemistry, Markey Cancer Center, and Sanders-Brown Center on AgingUniversity of KentuckyLexingtonUSA
  7. 7.Department of Clinical and Experimental MedicineUniversity of FoggiaFoggiaItaly

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