The BACH1/Nrf2 Axis in Brain in Down Syndrome and Transition to Alzheimer Disease-Like Neuropathology and Dementia
Abstract
:1. Genetics of Oxidative Stress in Down Syndrome
2. BACH1/Nrf2 Signaling
3. Involvement of BACH1 in AD and DS
4. Concluding Remarks
Funding
Conflicts of Interest
Abbreviations
Aβ | amyloid beta-peptide |
AD | Alzheimer disease |
APP | amyloid precursor protein |
ARE | antioxidant response element |
BACH1 | the transcription factor BTB and CNC homology 1 |
BVR-A | biliverdin reductase A |
CAT | catalase |
CBR | carbonyl reductase |
CO | carbon monoxide |
DS | Down syndrome |
DSAD | Down syndrome with Alzheimer disease |
ETS2 | the Protein C-ets-2 |
HNE | 4-hydroxy-2-nonenal |
HO-1 | heme oxygenase 1 |
HSA21 | human chromosome 21 |
Keap1 | Kelch-like ECH-Associating protein 1 |
MAPK | mitogen-activated protein kinase |
MAPT | microtubule associated protein tau |
NFT | neurofibrillary tangles |
NO | nitric oxide |
NQO1 | NADPH quinone oxidoreductase 1 |
Nrf2 | nuclear factor erythroid 2 related factor 2 |
OXOPHOS | oxidative phosphorylation |
OS | oxidative stress |
ROS | reactive oxygen species |
SOD1 | Cu, Zn superoxide dismutase 1 |
MnSOD | manganese superoxide dismutase |
SP | senile plaques |
S100B | S100 calcium-binding protein B |
References
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Gene on Hsa21 | Molecular Function | Biological Process | Relevance in Down Syndrome |
---|---|---|---|
SOD-1 (Cu,Zn-superoxide dismutase 1) | Oxidoreductase | Antioxidant Response | Triplication of SOD-1 in DS brain results in an imbalance in the ratio of SOD-1 to CAT and GPX (two enzymes involved in its metabolism), thus leading to the accumulation of H2O2 in the cells. |
APP (amyloid precursor protein) | Heparin-binding, Protease inhibitor | Apoptosis, Cell adhesion, Endocytosis, Notch signaling pathway and Aβ processing | Triplication of APP causes the over-production of Aβ (1-40/42) in DS brain. Deposition of senile plaques of Aβ is observed in post-mortem brain and plasma from DS compared with non-DS individuals. |
BACH1 (BTB Domain and CNC Homolog 1) | DNA-binding, Transcription regulation | Antioxidant Response | Triplication of BACH1, as a negative transcription regulator, in DS brain could block the induction of antioxidant genes, therefore promoting increased OS in the cell. |
CBR(Carbonyl reductase) | Oxidoreductase | Oxidative stress Response | Triplication of CBR in DS play a role in exacerbating OS. Carbonyls are toxic metabolic intermediates that are mainly detoxified by aldehyde dehydrogenase or reduced by CBR and/or alcohol dehydrogenase to their corresponding alcohols. Increased levels of these enzymes were detected in the brain of DS patients, likely in response to elevated carbonyls production in DS. |
ETS2(Protein C-ets-2) | Transcription regulation | Cell differentiation, maturation and signaling | Triplication of Ets-2 could play a role in the increased susceptibility of DS cells to undergo apoptosis given common pathophysiological features shared between Ets-2 overexpressing transgenic mice and individuals with DS. |
S100B(S100 calcium-binding protein B) | Ca2+-binding protein | Neurotrophic factor | Triplication of S100β in DS corresponds to an increase of its expression levels in astrocytes in association with neuritic plaques. In addition, chronic overexpression of S100β contributes to increased neuronal and neuritic βAPP expression with consequent accelerated amyloid deposition, as well as abnormal growth of neurites in β-amyloid plaques, similar to observations in middle-aged DS patients. |
Pathology | BACH1 Changes | References |
---|---|---|
Down Syndrome (DS) | ↑ BACH1 protein levels in fetal cortical specimens of human DS | Ferrando-Miguel R.J. Neural Transm Suppl, 2003(67): p. 193-205 Tili, E., et al., Ann Diagn Pathol, 2018. 34: p. 103-109. |
↑ BACH1 protein levels in human DS subjects, either before or after the development of AD | Di Domenico, F., et al., J.Alzheimers Dis, 2015. 44(4): p. 1107–20. | |
Changes in post-translational modifications of BACH-1: | Di Domenico, F., et al., J.Alzheimers Dis, 2015. 44(4): p. 1107–20. | |
↓ mono-ubiquitination of BACH1 in young DS human brain | ||
↑ poly-ubiquitinylation of BACH1 only in DSAD subjects | ||
↑ BACH1 protein levels in brain of Ts65Dn mice. | Di Domenico, F., et al., J.Alzheimers Dis, 2015. 44(4): p. 1107–20. | |
No changes were observed in BACH1 ubiquitination in Ts65Dn mice compared to euploid mice. | ||
Alzheimer Disease (AD) | NO changes were observed in BACH1 protein levels in AD brain. | Shim, K.S., R. Ferrando-Miguel, and G. Lubec, J Neural Transm Suppl, 2003(67): p. 39–49. |
↑ BACH1 protein levels in AD Brain using an immunohistochemistry approach. | Tili, E., et al., Ann Diagn Pathol, 2018. 34: p. 103–109. |
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Perluigi, M.; Tramutola, A.; Pagnotta, S.; Barone, E.; Butterfield, D.A. The BACH1/Nrf2 Axis in Brain in Down Syndrome and Transition to Alzheimer Disease-Like Neuropathology and Dementia. Antioxidants 2020, 9, 779. https://doi.org/10.3390/antiox9090779
Perluigi M, Tramutola A, Pagnotta S, Barone E, Butterfield DA. The BACH1/Nrf2 Axis in Brain in Down Syndrome and Transition to Alzheimer Disease-Like Neuropathology and Dementia. Antioxidants. 2020; 9(9):779. https://doi.org/10.3390/antiox9090779
Chicago/Turabian StylePerluigi, Marzia, Antonella Tramutola, Sara Pagnotta, Eugenio Barone, and D. Allan Butterfield. 2020. "The BACH1/Nrf2 Axis in Brain in Down Syndrome and Transition to Alzheimer Disease-Like Neuropathology and Dementia" Antioxidants 9, no. 9: 779. https://doi.org/10.3390/antiox9090779