Biliverdin reductase-A impairment links brain insulin resistance with increased Aβ production in an animal model of aging: Implications for Alzheimer disease

Francesca Triani, Antonella Tramutola, Fabio Di Domenico, Nidhi Sharma, D. Allan Butterfield, Elizabeth Head, Marzia Perluigi, Eugenio Barone

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Brain insulin resistance is associated with an increased Aβ production in AD although the molecular mechanisms underlying this link are still largely unknown. Biliverdin reductase-A (BVR-A) is a unique Ser/Thr/Tyr kinase regulating insulin signalling. Studies from our group, demonstrated that BVR-A impairment is among the earliest events favoring brain insulin resistance development. Furthermore, reported a negative association between BVR-A protein levels/activation and BACE1 protein levels in the parietal cortex of aged beagles (an animal model of AD), thus suggesting a possible interaction. Therefore, we aimed to demonstrate that BVR-A impairment is a molecular bridge linking brain insulin resistance with increased Aβ production. Age-associated changes of BVR-A, BACE1, insulin signalling cascade and APP processing were evaluated in the parietal cortex of beagles and experiments to confirm the hypothesized mechanism(s) have been performed in vitro in HEK293APPswe cells. Our results show that BVR-A impairment occurs early with age and is associated with brain insulin resistance. Furthermore, we demonstrate that BVR-A impairment favors CK1-mediated Ser phosphorylation of BACE1 (known to mediate BACE1 recycling to plasma membrane) along with increased Aβ production in the parietal cortex, with age. Overall, our results suggest that the impairment of BVR-A is an early molecular event contributing to both (I) the onset of brain insulin resistance and (II) the increased Aβ production observed in AD. We, therefore, suggest that by targeting BVR-A activity it could be possible to delay the onset of brain insulin resistance along with an improved regulation of the APP processing.

Original languageEnglish
Pages (from-to)3181-3194
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number10
DOIs
StatePublished - Oct 2018

Bibliographical note

Funding Information:
This work was supported by funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n° 624341 to EB and MP; by funding from Banca d'Italia n° 12868/17 to EB; by founding from the Ministry of Education, Universities and Research (MIUR) under the SIR program n° RBSI144MT to FDD; by funding from Fondi Ateneo grant funded by Sapienza University n° C26H15JT9X to MP. We thank Prof. Patrick Fraering (Foundation Eclosion Campus Biotech Innovation Park, Geneve) for kindly provide us with the HEK293APPswe cells used in this study.

Funding Information:
This work was supported by funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme ( FP7/2007-2013 ) under REA grant agreement n° 624341 to EB and MP; by funding from Banca d'Italia n° 12868/17 to EB; by founding from the Ministry of Education, Universities and Research (MIUR) under the SIR program n° RBSI144MT to FDD; by funding from Fondi Ateneo grant funded by Sapienza University n° C26H15JT9X to MP. We thank Prof. Patrick Fraering (Foundation Eclosion Campus Biotech Innovation Park, Geneve) for kindly provide us with the HEK293APPswe cells used in this study.

Publisher Copyright:
© 2018 Elsevier B.V.

Keywords

  • Alzheimer disease
  • BACE1
  • Bilivedin reductase-A
  • Canine
  • Dog
  • Insulin resistance

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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