Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer's brains is mediated by USP25.
Ontology highlight
ABSTRACT:
SUBMITTER: Zheng Q
PROVIDER: S-EPMC7775784 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundTrisomy 21 (T21) is associated with intellectual disability that ranges from mild to profound with an average intellectual quotient of around 50. Furthermore, T21 patients have a high risk of developing Alzheimer's disease (AD) early in life, characterized by the presence of senile plaques of amyloid protein and neurofibrillary tangles, leading to neuronal loss and cognitive decline. We postulate that epigenetic factors contribute to the observed variability in intellectual disability, as well as at the level of neurodegeneration seen in T21 individuals.Materials and methodsA genome-wide DNA methylation study was performed using Illumina Infinium® MethylationEPIC BeadChips on whole blood DNA of 3 male T21 patients with low IQ, 8 T21 patients with high IQ (4 males and 4 females), and 21 age- and sex-matched control samples (12 males and 9 females) in order to determine whether DNA methylation alterations could help explain variation in cognitive impairment between individuals with T21. In view of the increased risk of developing AD in T21 individuals, we additionally investigated the T21-associated sites in published blood DNA methylation data from the AgeCoDe cohort (German study on Ageing, Cognition, and Dementia). AgeCoDe represents a prospective longitudinal study including non-demented individuals at baseline of which a part develops AD dementia at follow-up.ResultsTwo thousand seven hundred sixteen differentially methylated sites and regions discriminating T21 and healthy individuals were identified. In the T21 high and low IQ comparison, a single CpG located in the promoter of PELI1 was differentially methylated after multiple testing adjustment. For the same contrast, 69 differentially methylated regions were identified. Performing a targeted association analysis for the significant T21-associated CpG sites in the AgeCoDe cohort, we found that 9 showed significant methylation differences related to AD dementia, including one in the ADAM10 gene. This gene has previously been shown to play a role in the prevention of amyloid plaque formation in the brain.ConclusionThe differentially methylated regions may help understand the interaction between methylation alterations and cognitive function. In addition, ADAM10 might be a valuable blood-based biomarker for at least the early detection of AD.
| S-EPMC6916110 | biostudies-literature
Project description:Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer's disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl.
| S-EPMC5570437 | biostudies-other
Project description:Retina is a crucial tissue for capturing and processing light stimulus. It is critical to describe the characteristics of retina at the single-cell level for understanding its biological functions. A variety of abnormalities in terms of morphology and function are present in the trisomy 21 (T21) retina. To evaluate the consequences of chromosome aneuploidy on retina development, we identified the single-cell transcriptional profiles of a T21 fetus and performed comprehensive bioinformatic analyses. Our data revealed the diversity and heterogeneity of cellular compositions in T21 retina, as well as the abnormal constitution of T21 retina compared to disomic retina. In total, we identified seven major cell types and several subtypes within each cell type, followed by the detection of corresponding molecular markers, including previously reported ones and a series of novel markers. Through the analysis of the retinal differentiation process, subtypes of retinal progenitor cells (RPCs) exhibiting the potential of different retinal cell-type commitments and certain Müller glial cells (MGs) with differentiating potency were identified. Moreover, the extensive communication networks between cellular types were confirmed, among which a few ligand-receptor interactions were related to the formation and function of retina and immunoregulatory interactions. Taken together, our data provides the first ever single-cell transcriptome profiles for human T21 retina, which facilitates the understanding on the dosage effects of chromosome 21 on the development of retina.
| S-EPMC7538860 | biostudies-literature
Project description:The most common live-born human aneuploidy is trisomy 21, which causes Down syndrome (DS). Dosage imbalance of genes on chromosome 21 (Hsa21) affects complex gene-regulatory interactions and alters development to produce a wide range of phenotypes, including characteristic facial dysmorphology. Little is known about how trisomy 21 alters craniofacial morphogenesis to create this characteristic appearance. Proponents of the "amplified developmental instability" hypothesis argue that trisomy 21 causes a generalized genetic imbalance that disrupts evolutionarily conserved developmental pathways by decreasing developmental homeostasis and precision throughout development. Based on this model, we test the hypothesis that DS faces exhibit increased developmental instability relative to euploid individuals. Developmental instability was assessed by a statistical analysis of fluctuating asymmetry. We compared the magnitude and patterns of fluctuating asymmetry among siblings using three-dimensional coordinate locations of 20 anatomic landmarks collected from facial surface reconstructions in four age-matched samples ranging from 4 to 12 years: (1) DS individuals (n?=?55); (2) biological siblings of DS individuals (n?=?55); 3) and 4) two samples of typically developing individuals (n?=?55 for each sample), who are euploid siblings and age-matched to the DS individuals and their euploid siblings (samples 1 and 2). Identification in the DS sample of facial prominences exhibiting increased fluctuating asymmetry during facial morphogenesis provides evidence for increased developmental instability in DS faces. We found the highest developmental instability in facial structures derived from the mandibular prominence and lowest in facial regions derived from the frontal prominence.
| S-EPMC3744194 | biostudies-literature
Project description:Down's syndrome is a common disorder with enormous medical and social costs, caused by trisomy for chromosome 21. We tested the concept that gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST (the X-inactivation gene). Using genome editing with zinc finger nucleases, we inserted a large, inducible XIST transgene into the DYRK1A locus on chromosome 21, in Down's syndrome pluripotent stem cells. The XIST non-coding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation to form a 'chromosome 21 Barr body'. This provides a model to study human chromosome inactivation and creates a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing one chromosome 21. Successful trisomy silencing in vitro also surmounts the major first step towards potential development of 'chromosome therapy'.
| S-EPMC3848249 | biostudies-literature
Project description:Trisomy for human chromosome 21 (Hsa21) results in Down syndrome (DS). The finished human genome sequence provides a thorough catalog of the genetic elements whose altered dosage perturbs development and function in DS. However, understanding how small alterations in the steady state transcript levels for <2% of human genes can disrupt development and function of essentially every cell presents a more complicated problem. Mouse models that recapitulate specific aspects of DS have been used to identify changes in brain morphogenesis and function. Here we provide a few examples of how trisomy for specific genes affects the development of the cortex and cerebellum to illustrate how gene dosage effects might contribute to divergence between the trisomic and euploid brains.
| S-EPMC3273608 | biostudies-literature
Project description:Alzheimer's disease (AD) is characterized by progressive neurodegeneration associated with the aggregation and deposition of ?-amyloid (A?(40) and A?(42) ) peptide in senile plaques. Recent studies suggest that copper may play an important role in AD pathology. Copper concentrations are elevated in amyloid plaques and copper binds with high affinity to the A? peptide and promotes A? oligomerization and neurotoxicity. Despite this connection between copper and AD, it is unknown whether the expression of proteins involved in regulating copper homeostasis is altered in this disorder. In this study, we demonstrate that the copper transporting P-type ATPase, ATP7A, is highly expressed in activated microglial cells that are specifically clustered around amyloid plaques in the TgCRND8 mouse model of AD. Using a cultured microglial cell line, ATP7A expression was found to be increased by the pro-inflammatory cytokine interferon-gamma, but not by TNF-? or IL-1?. Interferon-gamma also elicited marked changes in copper homeostasis, including copper-dependent trafficking of ATP7A from the Golgi to cytoplasmic vesicles, increased copper uptake and elevated expression of the CTR1 copper importer. These findings suggest that pro-inflammatory conditions associated with AD cause marked changes in microglial copper trafficking, which may underlie the changes in copper homeostasis in AD. It is concluded that copper sequestration by microglia may provide a neuroprotective mechanism in AD.
| S-EPMC2945454 | biostudies-literature
Project description:BackgroundMolecular size determination of circulating free fetal DNA in maternal plasma is an important detection method for noninvasive prenatal testing (NIPT). The fetal DNA molecule is the primary factor determining the overall performance of NIPT and its clinical interpretation. The proportion of cell-free fetal DNA molecules is expressed as the fetal DNA fraction in the plasma of pregnant women.MethodsWe proposed an effective method to deduce fetal chromosomal aneuploidy based on the proportion of a certain range of DNA fragment lengths from maternal plasma. We gradually narrowed the range of the upper and lower boundary via a traversing algorithm.ResultsWe explored the optimal range of the upper and lower boundary by using size-based DNA fragment length. Using this range, the accuracy of the sensitivity and specificity could be improved by up to 100% for detecting the three most common autosomal aneuploidies, namely trisomy 13, trisomy 18, trisomy 21 in the sample set.ConclusionsNumerical experiments demonstrate that our method is effective and efficient. The program is available upon request.
| S-EPMC6461288 | biostudies-literature
Project description:Despite the prevalence of Down syndrome (DS), little is known regarding the specific cell pathologies that underlie this multi-system disorder. To understand which cell types and pathways are more directly affected by trisomy 21 (T21), we used an inducible-XIST system to silence one chromosome 21 in vitro. T21 caused the dysregulation of Notch signaling in iPSCs, potentially affecting cell-type programming. Further analyses identified dysregulation of pathways important for two cell types: neurogenesis and angiogenesis. Angiogenesis is essential to many bodily systems, yet is understudied in DS; therefore, we focused next on whether T21 affects endothelial cells. An in vitro assay for microvasculature formation revealed a cellular pathology involving delayed tube formation in response to angiogenic signals. Parallel transcriptomic analysis of endothelia further showed deficits in angiogenesis regulators. Results indicate a direct cell-autonomous impact of T21 on endothelial function, highlighting the importance of angiogenesis, with wide-reaching implications for development and disease progression.
| S-EPMC9505374 | biostudies-literature
Project description:In Alzheimer's disease, aggregates of A? and tau in amyloid plaques and neurofibrillary tangles spread progressively across brain tissues following a characteristic pattern, implying a tissue-specific vulnerability to the disease. We report a transcriptional analysis of healthy brains and identify an expression signature that predicts-at ages well before the typical onset-the tissue-specific progression of the disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the expression patterns of the proteins that coaggregate in amyloid plaques and neurofibrillary tangles, together with those of the protein homeostasis components that regulate A? and tau. Because this expression signature is evident in healthy brains, our analysis provides an explanatory link between a tissue-specific environmental risk of protein aggregation and a corresponding vulnerability to Alzheimer's disease.
| S-EPMC4980108 | biostudies-literature