scholarly journals The BACH1/Nrf2 Axis in Brain in Down Syndrome and Transition to Alzheimer Disease-Like Neuropathology and Dementia

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 779
Author(s):  
Marzia Perluigi ◽  
Antonella Tramutola ◽  
Sara Pagnotta ◽  
Eugenio Barone ◽  
D. Allan Butterfield
Keyword(s):  
Down Syndrome ◽  
Senile Plaques ◽  
Redox Homeostasis ◽  
Antioxidant Defense System ◽  
Chromosome 21 ◽  
Potential Contribution ◽  
Physiological Relevance ◽  
Increased Risk ◽  
Hyperphosphorylated Tau Protein ◽  
The Brain

Down syndrome (DS) is the most common genetic cause of intellectual disability that is associated with an increased risk to develop early-onset Alzheimer-like dementia (AD). The brain neuropathological features include alteration of redox homeostasis, mitochondrial deficits, inflammation, accumulation of both amyloid beta-peptide oligomers and senile plaques, as well as aggregated hyperphosphorylated tau protein-containing neurofibrillary tangles, among others. It is worth mentioning that some of the triplicated genes encoded are likely to cause increased oxidative stress (OS) conditions that are also associated with reduced cellular responses. Published studies from our laboratories propose that increased oxidative damage occurs early in life in DS population and contributes to age-dependent neurodegeneration. This is the result of damaged, oxidized proteins that belong to degradative systems, antioxidant defense system, neuronal trafficking. and energy metabolism. This review focuses on a key element that regulates redox homeostasis, the transcription factor Nrf2, which is negatively regulated by BACH1, encoded on chromosome 21. The role of the Nrf2/BACH1 axis in DS is under investigation, and the effects of triplicated BACH1 on the transcriptional regulation of Nrf2 are still unknown. In this review, we discuss the physiological relevance of BACH1/Nrf2 signaling in the brain and how the dysfunction of this system affects the redox homeostasis in DS neurons and how this axis may contribute to the transition of DS into DS with AD neuropathology and dementia. Further, some of the evidence collected in AD regarding the potential contribution of BACH1 to neurodegeneration in DS are also discussed.

scholarly journals Intracerebral haemorrhage in Down syndrome: protected or predisposed?

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 876 ◽  
Author(s):  
Lewis Buss ◽  
Elizabeth Fisher ◽  
John Hardy ◽  
Dean Nizetic ◽  
Jurgen Groet ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Intracerebral Haemorrhage ◽  
Early Onset ◽  
Epidemiological Data ◽  
Haemorrhagic Stroke ◽  
Brain Parenchyma ◽  
Chromosome 21 ◽  
Clinical Consequence ◽  
Increased Risk ◽  
The Central Nervous System

Down syndrome (DS), which arises from trisomy of chromosome 21, is associated with deposition of large amounts of amyloid within the central nervous system. Amyloid accumulates in two compartments: as plaques within the brain parenchyma and in vessel walls of the cerebral microvasculature. The parenchymal plaque amyloid is thought to result in an early onsetAlzheimer’s disease (AD) dementia, a phenomenon so common amongst people with DS that it could be considered a defining feature of the condition. The amyloid precursor protein (APP) gene lies on chromosome 21 and its presence in three copies in DS is thought to largely drive the early onset AD. In contrast, intracerebral haemorrhage (ICH), the main clinical consequence of vascular amyloidosis, is a more poorly defined feature of DS. We review recent epidemiological data on stroke (including haemorrhagic stroke) in order to make comparisons with a rare form of familial AD due to duplication (i.e. having three copies) of the APP region on chromosome 21, here called ‘dup-APP’, which is associated with more frequent and severe ICH. We conclude that although people with DS are at increased risk of ICH, this is less common than in dup-APP, suggesting the presence of mechanisms that act protectively. We review these mechanisms and consider comparative research into DS and dup-APP that may yield further pathophysiological insight.

scholarly journals Ten Reasons Why People With Down Syndrome are Protected From the Development of Most Solid Tumors -A Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Marta Pilar Osuna-Marco ◽  
Mónica López-Barahona ◽  
Blanca López-Ibor ◽  
Águeda Mercedes Tejera
Keyword(s):  
Down Syndrome ◽  
Solid Tumors ◽  
Tumor Suppressor Genes ◽  
Wilms Tumor ◽  
Extra Chromosome ◽  
Germ Cell Tumors ◽  
Chromosome 21 ◽  
Testicular Tumors ◽  
Unique Pattern ◽  
Increased Risk

People with Down syndrome have unique characteristics as a result of the presence of an extra chromosome 21. Regarding cancer, they present a unique pattern of tumors, which has not been fully explained to date. Globally, people with Down syndrome have a similar lifetime risk of developing cancer compared to the general population. However, they have a very increased risk of developing certain tumors (e.g., acute leukemia, germ cell tumors, testicular tumors and retinoblastoma) and, on the contrary, there are some other tumors which appear only exceptionally in this syndrome (e.g., breast cancer, prostate cancer, medulloblastoma, neuroblastoma and Wilms tumor). Various hypotheses have been developed to explain this situation. The genetic imbalance secondary to the presence of an extra chromosome 21 has molecular consequences at several levels, not only in chromosome 21 but also throughout the genome. In this review, we discuss the different proposed mechanisms that protect individuals with trisomy 21 from developing solid tumors: genetic dosage effect, tumor suppressor genes overexpression, disturbed metabolism, impaired neurogenesis and angiogenesis, increased apoptosis, immune system dysregulation, epigenetic aberrations and the effect of different microRNAs, among others. More research into the molecular pathways involved in this unique pattern of malignancies is still needed.

scholarly journals Glutathione in the Brain

2021 ◽  
Vol 22 (9) ◽  
pp. 5010
Author(s):  
Koji Aoyama
Keyword(s):  
Neurodegenerative Diseases ◽  
Regulatory Mechanism ◽  
Excitatory Amino Acid ◽  
Redox Homeostasis ◽  
Disease Onset ◽  
Glutamate Transporter ◽  
Antioxidant Defense System ◽  
Common Finding ◽  
Potential Therapeutic Application ◽  
The Brain

Glutathione (GSH) is the most abundant non-protein thiol, and plays crucial roles in the antioxidant defense system and the maintenance of redox homeostasis in neurons. GSH depletion in the brain is a common finding in patients with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and can cause neurodegeneration prior to disease onset. Excitatory amino acid carrier 1 (EAAC1), a sodium-dependent glutamate/cysteine transporter that is selectively present in neurons, plays a central role in the regulation of neuronal GSH production. The expression of EAAC1 is posttranslationally controlled by the glutamate transporter-associated protein 3–18 (GTRAP3-18) or miR-96-5p in neurons. The regulatory mechanism of neuronal GSH production mediated by EAAC1 may be a new target in therapeutic strategies for these neurodegenerative diseases. This review describes the regulatory mechanism of neuronal GSH production and its potential therapeutic application in the treatment of neurodegenerative diseases.

scholarly journals Prenatal Evaluation of MicroRNA Expressions in Pregnancies with Down Syndrome

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Biray Erturk ◽  
Emin Karaca ◽  
Ayca Aykut ◽  
Burak Durmaz ◽  
Ahmet Guler ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Prenatal Testing ◽  
Maternal Plasma ◽  
Chromosome 21 ◽  
Screening Tests ◽  
Sonographic Examination ◽  
Noninvasive Prenatal Testing ◽  
Abnormal Finding ◽  
Expression Levels ◽  
Increased Risk

Background. Currently, the data available on the utility of miRNAs in noninvasive prenatal testing is insufficient in the literature. We evaluated the expression levels of 14 miRNAs located on chromosome 21 in maternal plasma and their utility in noninvasive prenatal testing of Down Syndrome.Method. A total of 56 patients underwent invasive prenatal testing; 23 cases were carrying Down Syndrome affected fetuses, and 33 control cases carrying unaffected, normal karyotype fetuses were included for comparison. Indications for invasive prenatal testing were advanced maternal age, increased risk of Down Syndrome in screening tests, and abnormal finding in the sonographic examination. In both the study and control groups, all the pregnant women were at 17th and 18th week of gestation. miRNA expression levels were measured using real-time RT-PCR.Results. Significantly increased maternal plasma levels of miR-3156 and miR-99a were found in the women carrying a fetus with Down Syndrome.Conclusion. Our results provide a basis for multicenter studies with larger sample groups and microRNA profiles, particularly with the microRNAs which were found to be variably expressed in our study. Through this clinical research, the utility of microRNAs in noninvasive prenatal testing can be better explored in future studies.

scholarly journals Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 767-775 ◽  
Author(s):  
Gina Kirsammer ◽  
Sarah Jilani ◽  
Hui Liu ◽  
Elizabeth Davis ◽  
Sandeep Gurbuxani ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Gene Dosage ◽  
Hematologic Malignancies ◽  
Chromosome 21 ◽  
Myeloproliferative Disease ◽  
Ts65dn Mouse ◽  
Hematopoietic Stem ◽  
Megakaryoblastic Leukemia ◽  
Increased Risk

Children with Down syndrome (DS) display macrocytosis, thrombocytosis, and a 500-fold increased risk of developing megakaryocytic leukemia; however, the specific effects of trisomy 21 on hematopoiesis remain poorly defined. To study this question, we analyzed blood cell development in the Ts65Dn mouse model of DS. Ts65Dn mice are trisomic for 104 orthologs of Hsa21 genes and are the most widely used mouse model for DS. We discovered that Ts65Dn mice display persistent macrocytosis and develop a myeloproliferative disease (MPD) characterized by profound thrombocytosis, megakaryocyte hyperplasia, dysplastic megakaryocyte morphology, and myelofibrosis. In addition, these animals bear distorted hematopoietic stem and myeloid progenitor cell compartments compared with euploid control littermates. Of the 104 trisomic genes in Ts65Dn mice, Aml1/Runx1 attracts considerable attention as a candidate oncogene in DS–acute megakaryoblastic leukemia (DS-AMKL). To determine whether trisomy for Aml1/Runx1 is essential for MPD, we restored disomy at the Aml1/Runx1 locus in the Ts65Dn strain. Surprisingly, trisomy for Aml1/Runx1 is not required for megakaryocyte hyperplasia and myelofibrosis, suggesting that trisomy for one or more of the remaining genes can promote this disease. Our studies demonstrate the potential of DS mouse models to improve our understanding of chromosome 21 gene dosage effects in human hematologic malignancies.

scholarly journals Mapping the cellular origin and early evolution of leukemia in Down syndrome

Science ◽  
2021 ◽  
Vol 373 (6551) ◽  
pp. eabf6202 ◽  
Author(s):  
Elvin Wagenblast ◽  
Joana Araújo ◽  
Olga I. Gan ◽  
Sarah K. Cutting ◽  
Alex Murison ◽  
...  
Keyword(s):  
Stem Cells ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Chromosome 21 ◽  
Hematopoietic Stem ◽  
Developmental Context ◽  
Cellular Origin ◽  
Increased Risk ◽  
Stem And Progenitor Cells

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.

scholarly journals Administration of Mucuna Beans (Mucuna Pruriences (L.) DC. Var. Utilis) Improves Cognition and Neuropathology of 3×Tg-AD Mice

2021 ◽  
Author(s):  
Fumiko Konishi ◽  
Tadasu Furusho ◽  
Yoshiyuki Soeda ◽  
Jun Yamauchi ◽  
Shoko Kobayashi ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Control Group ◽  
Phosphorylated Tau ◽  
Aβ Oligomers ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
Hyperphosphorylated Tau Protein ◽  
Ad Prevention ◽  
The Brain

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid-beta peptides (Aβ) resulting in senile plaques and intracellular hyperphosphorylated tau protein resulting in neurofibrillary tangles (NFTs). Mucuna beans (Mucuna pruriences (L.) DC. var. utilis) are unique plants containing 3%–9% L-3,4-dihydroxyphenylalanine (L-DOPA). Here we investigated the effect of the administration of Mucuna beans on AD prevention by feeding triple-transgenic mice (3×Tg-AD mice) with a diet containing Mucuna beans for 13 months. The levels of Aβ oligomers and detergent-insoluble phosphorylated tau decreased in the brain of mice fed with Mucuna beans (Mucuna group) compared to those of the Control group. Aβ accumulation and phosphorylated tau accumulation in the brain in the Mucuna group were also reduced. In addition, administration of Mucuna beans improved cognitive function. These results suggest that administration of Mucuna beans may have a preventive effect on AD development in 3×Tg-AD mice.

scholarly journals Endosomal structure and APP biology are not altered in preclinical cellular models of Down syndrome

2021 ◽  
Author(s):  
Claudia Cannavo ◽  
Karen Cleverley ◽  
Cheryl Maduro ◽  
Paige Mumford ◽  
Dale Moulding ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Cell Biology ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
App Processing ◽  
Cellular Models ◽  
Increased Risk ◽  
Primary Mouse

Individuals who have Down syndrome (trisomy 21) are at greatly increased risk of developing Alzheimer’s disease – dementia. Alzheimer’s disease is characterised by the accumulation in the brain of amyloid-β plaques that are a product of amyloid precursor protein, encoded by the APP gene on chromosome 21. In Down syndrome the first site of amyloid-β accumulation is within endosomes and changes to endosome biology occur early in disease. Here we determine if primary mouse embryonic fibroblasts isolated from two mouse models of Down syndrome can be used to study endosome and APP cell biology. We report that in these cellular models of Down syndrome endosome number, size and APP processing are not altered, likely because APP is not dosage sensitive in these models, despite three copies of App .

scholarly journals Mapping the Cellular Origin and Early Evolution of Leukemia in Down Syndrome

2020 ◽  
Author(s):  
Elvin Wagenblast ◽  
Joana Araújo ◽  
Olga I. Gan ◽  
Sarah K. Cutting ◽  
Alex Murison ◽  
...  
Keyword(s):  
Stem Cells ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Fetal Liver ◽  
Chromosome 21 ◽  
Hematopoietic Stem ◽  
Cellular Origin ◽  
Increased Risk ◽  
Stem And Progenitor Cells ◽  
Cellular Context

AbstractChildren with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. As Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal liver hematopoietic cells and xenotransplantation. GATA1 mutations caused transient preleukemia only when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 miRNAs triggers predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT cells mediated the propagation of preleukemia and leukemia, and functional KIT inhibition targeted preleukemic stem cells, blocking progression to leukemia.

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