Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 44, Issue 4, Pages 1107-1120Publisher
IOS PRESS
DOI: 10.3233/JAD-141254
Keywords
Bach1; biliverdin reductase; heme oxygenase; oxidative stress; trisomy 21
Categories
Funding
- fondi di Ateneo Sapienza
- NIH [AG-05119]
- European Union [624341]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Institute on Aging [NIH 1RO1HD064993-01]
- NICHD Brain and Tissue Bank for Developmental Disorders of the University of Maryland, Baltimore, MD [HHSN275200900011C (N01HD90011)]
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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.
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