Bach1 overexpression in Down syndrome correlates with the alteration of the HO-1/BVR-a system: insights for transition to Alzheimer's disease

Topic: Brain proteins, microglia and lab models

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.

@article{didomenico2015-25391381,
  author  = {Di Domenico, F. and Pupo, G. and Mancuso, C. and Barone, E. and Paolini, F. and Arena, A. and Blarzino, C. and Schmitt, F. A. and others},
  title   = {{Bach1 overexpression in Down syndrome correlates with the alteration of the HO-1/BVR-a system: insights for transition to Alzheimer's disease}},
  journal = {Journal of Alzheimer's disease : JAD},
  year    = {2015},
  doi     = {10.3233/jad-141254},
  pmid    = {25391381},
  url     = {https://doi.org/10.3233/jad-141254}
}

Key findings

• 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.

Why it matters

In brain tissue from all Down syndrome cases studied, total Bach1 protein levels were increased along with reduced induction of HO-1, and the development of Alzheimer's disease in Down syndrome was characterized by increased Bach1, increased HO-1 and increased nitration of BVR-A with reduced activity. The findings were also examined in the Ts65Dn mouse model at 3 and 15 months of age.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.3233/jad-141254
• PubMed: 25391381
• Original source →
• Free full text: IRIS Research product catalog (Sapienza University of Rome) →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Amyloid β-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression Antioxidants & redox signaling · 2013-02-14 · usefulness score 48/100 · Risk genes beyond APOE
• Biomarkers of oxidative stress are significantly elevated in Down syndrome Free radical biology & medicine · 1998-12-01 · usefulness score 47/100 · Down syndrome and Alzheimer's
• Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome Biochimica et biophysica acta · 2011-10-08 · usefulness score 47/100 · Down syndrome and Alzheimer's
• Oxidative Stress and Down Syndrome: A Route toward Alzheimer-Like Dementia Current gerontology and geriatrics research · 2011-11-29 · usefulness score 46/100 · Down syndrome and Alzheimer's
• Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain Biochimica et biophysica acta · 2014-04-13 · usefulness score 45/100 · Down syndrome and Alzheimer's
• Redox proteomics analysis to decipher the neurobiology of Alzheimer-like neurodegeneration: overlaps in Down's syndrome and Alzheimer's disease brain The Biochemical journal · 2014-10-01 · usefulness score 45/100 · Down syndrome and Alzheimer's
• Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down Syndrome: quantitative comparison with Alzheimer dementia Annals of neurology · 1980-05-01 · usefulness score 43/100 · Down syndrome and Alzheimer's
• Redox proteomics analysis of HNE-modified proteins in Down syndrome brain: clues for understanding the development of Alzheimer disease Free radical biology & medicine · 2014-03-25 · usefulness score 43/100 · Down syndrome and Alzheimer's
• Protein expression of BACE1, BACE2 and APP in Down syndrome brains Amino acids · 2007-12-29 · usefulness score 42/100 · Down syndrome and Alzheimer's
• Beta-amyloid, oxidative stress and down syndrome Current Alzheimer research · 2006-12-01 · usefulness score 39/100 · Down syndrome and Alzheimer's
• Risk factors for dementia in people with down syndrome: issues in assessment and diagnosis American journal of mental retardation : AJMR · 2004-03-01 · usefulness score 38/100 · Down syndrome and Alzheimer's
• Differential susceptibility to neurofibrillary pathology among patients with Down syndrome Dementia (Basel, Switzerland) · 1996-05-01 · usefulness score 36/100 · Down syndrome and Alzheimer's

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• Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease Nature reviews. Neuroscience · 2019-03-01 · usefulness score 57/100 · Mild cognitive impairment
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• Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer's Disease Journal of Alzheimer's disease : JAD · 2018-01-01 · usefulness score 50/100 · Mild cognitive impairment
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• Chronic PERK induction promotes Alzheimer-like neuropathology in Down syndrome: Insights for therapeutic intervention Progress in neurobiology · 2020-08-11 · usefulness score 44/100 · Down syndrome and Alzheimer's
• Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in down syndrome Free radical biology & medicine · 2021-01-29 · usefulness score 43/100 · Down syndrome and Alzheimer's

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• Lecanemab and Vascular-Amyloid Deposition in Brains of People With Down Syndrome JAMA neurology · 2024-10-01 · usefulness score 53/100 · Down syndrome and Alzheimer's
• The Alzheimer amyloid precursor protein maps to human chromosome 21 bands q21.105-q21.05 Genomics · 1989-07-01 · usefulness score 39/100 · Down syndrome and Alzheimer's
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