Bach1 Overexpression in Down Syndrome Correlates with the Alteration of the HO-1/BVR-A System: Insights for Transition to Alzheimer's Disease

Article type: Research Article

Authors: Di Domenico, Fabio^a | Pupo, Gilda^a | Mancuso, Cesare^b | Barone, Eugenio^a | Paolini, Francesca^c | Arena, Andrea^a | Blarzino, Carla^a | Schmitt, Frederick A.^{d; e} | Head, Elizabeth^{d; f} | Butterfield, D. Allan^{d; g} | Perluigi, Marzia^{a; *}

Affiliations: [a] Department of Biochemical Sciences, Sapienza University of Rome, Italy | [b] Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy | [c] Laboratory of Virology, Regina Elena National Cancer Institute, Rome, Italy | [d] Sanders-Brown Centre of Aging, University of Kentucky, Lexington, KY, USA | [e] Department of Neurology, University of Kentucky, Lexington, KY, USA | [f] Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, KY, USA | [g] Department of Chemistry, University of Kentucky, Lexington, KY, USA

Correspondence: [*] Correspondence to: Marzia Perluigi, Department of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University of Rome, P.le Aldo Moro, 5 00185 Rome, Italy. Tel.: +39 0649910885; Fax: +39 064440062; E-mail: [email protected].

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.

Keywords: Bach1, biliverdin reductase, heme oxygenase, oxidative stress, trisomy 21

DOI: 10.3233/JAD-141254

Journal: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1107-1120, 2015