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 Cassano, Marzia Perluigi

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


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.

Original languageEnglish
Pages (from-to)2922-2943
Number of pages22
JournalMolecular Neurobiology
Issue number4
StatePublished - Apr 1 2019

Bibliographical note

Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.


  • Alzheimer disease
  • Biliverdin reductase-A
  • Insulin resistance
  • Intranasal
  • Neuroprotection

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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