Bach1 overexpression in down syndrome correlates with the alteration of the HO-1/BVR-A system: Insights for transition to alzheimer's disease

Fabio Di Domenico, Gilda Pupo, Cesare Mancuso, Eugenio Barone, Francesca Paolini, Andrea Arena, Carla Blarzino, Frederick A. Schmitt, Elizabeth Head, D. Allan Butterfield, Marzia Perluigi

Research output: Contribution to journalArticlepeer-review

Abstract

Bach1, among the genes encoded on chromosome 21, is a transcription repressor, which binds to antioxidant response elements of DNA thus inhibiting the transcription of specific genes involved in the cell stress response including heme oxygenase-1 (HO-1). HO-1 and its partner, biliverdin reductase-A (BVR-A), are upregulated in response to oxidative stress in order to protect cells against further damage. Since oxidative stress is an early event in Down syndrome (DS) and might contribute to the development of multiple deleterious DS phenotypes, including Alzheimer's disease (AD) pathology, we investigated the status of the Bach1/HO-1/BVR-A axis in DS and its possible implications for the development of AD. In the present study, we showed increased total Bach1 protein levels in the brain of all DS cases coupled with reduced induction of brain HO-1. Furthermore, increased oxidative stress could, on one hand, overcome the inhibitory effects of Bach1 and, on the other hand, promote BVR-A impairment. Our data show that the development of AD in DS subjects is characterized by (i) increased Bach1 total and poly-ubiquitination; (ii) increased HO-1 protein levels; and (iii) increased nitration of BVR-A followed by reduced activity. To corroborate our findings, we analyzed Bach1, HO-1, and BVR-A status in the Ts65Dn mouse model at 3 (young) and 15 (old) months of age. The above data support the hypothesis that the dysregulation of HO-1/BVR-A system contributes to the early increase of oxidative stress in DS and provide potential mechanistic paths involved in the neurodegenerative process and AD development.

Original languageEnglish
Pages (from-to)1107-1120
Number of pages14
JournalJournal of Alzheimer's Disease
Volume44
Issue number4
DOIs
Publication statusPublished - 2015

Keywords

  • Bach1
  • biliverdin reductase
  • heme oxygenase
  • oxidative stress
  • trisomy 21

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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