Bach1 overexpression in Down syndrome correlates with the alteration of the HO-1/BVR-a system: insights for transition to Alzheimer's disease.
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.
Department of Biochemical Sciences, Sapienza University of Rome, Italy.
Fabio
F
Di Domenico
Department of Biochemical Sciences, Sapienza University of Rome, Italy.
Gilda
G
Pupo
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.
Cesare
C
Mancuso
Department of Biochemical Sciences, Sapienza University of Rome, Italy.
Eugenio
E
Barone
Laboratory of Virology, Regina Elena National Cancer Institute, Rome, Italy.
Francesca
F
Paolini
Department of Biochemical Sciences, Sapienza University of Rome, Italy.
Andrea
A
Arena
Department of Biochemical Sciences, Sapienza University of Rome, Italy.
Carla
C
Blarzino
Sanders-Brown Centre of Aging, University of Kentucky, Lexington, KY, USA Department of Neurology, University of Kentucky, Lexington, KY, USA.
Frederick A
FA
Schmitt
Sanders-Brown Centre of Aging, University of Kentucky, Lexington, KY, USA Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, KY, USA.
Elizabeth
E
Head
Sanders-Brown Centre of Aging, University of Kentucky, Lexington, KY, USA Department of Chemistry, University of Kentucky, Lexington, KY, USA.
D Allan
DA
Butterfield
Department of Biochemical Sciences, Sapienza University of Rome, Italy.
Marzia
M
Perluigi
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002648:Child; D004314:Down Syndrome / Q000473:pathology; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics; D055815:Young Adult
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase
Bach1; biliverdin reductase; heme oxygenase; oxidative stress; trisomy 21