Similar Datasets
Project description:While challenging, identifying individuals displaying resilience to Alzheimer’s disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Recent studies indicate that somatic mutations in hematopoietic cells may lead to both the instigation and resilience to neurodegeneration. Down syndrome (DS), or trisomy 21, is the most significant genetic risk factor for AD. Interestingly, some DS individuals show resilience to AD neuropathology and do not exhibit dementia signs. Notably, DS individuals face a heightened risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Microglia dysfunction is a central mechanism in AD etiology. Here we hypothesize that somatic mutations associated with DS myeloid leukemia may impart resilience to microglia against AD. Using CRISPR-Cas9 gene editing, we introduce a DS-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-based in vitro microglia culture and in vivo human microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses type-1 interferon signaling in both DS and control human microglia, independent of trisomy 21 genetic background. This mutation also reduces neuroinflammation and enhances phagocytic and autophagy functions, ameliorating senescent and dystrophic changes in human microglia. Furthermore, the CSF2RB A455D mutation promotes the development of a microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize, outcompete, and gradually replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest the potential use of hPSC-derived CSF2RB A455D microglia to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need of depleting endogenous senescent microglia prior to cell transplantation.
2025-11-24 | GSE280913 | GEO
Project description:While challenging, identifying individuals displaying resilience to Alzheimer’s disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Recent studies indicate that somatic mutations in hematopoietic cells may lead to both the instigation and resilience to neurodegeneration. Down syndrome (DS), or trisomy 21, is the most significant genetic risk factor for AD. Interestingly, some DS individuals show resilience to AD neuropathology and do not exhibit dementia signs. Notably, DS individuals face a heightened risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Microglia dysfunction is a central mechanism in AD etiology. Here we hypothesize that somatic mutations associated with DS myeloid leukemia may impart resilience to microglia against AD. Using CRISPR-Cas9 gene editing, we introduce a DS-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-based in vitro microglia culture and in vivo human microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses type-1 interferon signaling in both DS and control human microglia, independent of trisomy 21 genetic background. This mutation also reduces neuroinflammation and enhances phagocytic and autophagy functions, ameliorating senescent and dystrophic changes in human microglia. Furthermore, the CSF2RB A455D mutation promotes the development of a microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize, outcompete, and gradually replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest the potential use of hPSC-derived CSF2RB A455D microglia to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need of depleting endogenous senescent microglia prior to cell transplantation.
2025-11-24 | GSE252237 | GEO
Project description:While challenging, identifying individuals displaying resilience to Alzheimer’s disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Recent studies indicate that somatic mutations in hematopoietic cells may lead to both the instigation and resilience to neurodegeneration. Down syndrome (DS), or trisomy 21, is the most significant genetic risk factor for AD. Interestingly, some DS individuals show resilience to AD neuropathology and do not exhibit dementia signs. Notably, DS individuals face a heightened risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Microglia dysfunction is a central mechanism in AD etiology. Here we hypothesize that somatic mutations associated with DS myeloid leukemia may impart resilience to microglia against AD. Using CRISPR-Cas9 gene editing, we introduce a DS-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-based in vitro microglia culture and in vivo human microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses type-1 interferon signaling in both DS and control human microglia, independent of trisomy 21 genetic background. This mutation also reduces neuroinflammation and enhances phagocytic and autophagy functions, ameliorating senescent and dystrophic changes in human microglia. Furthermore, the CSF2RB A455D mutation promotes the development of a microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize, outcompete, and gradually replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest the potential use of hPSC-derived CSF2RB A455D microglia to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need of depleting endogenous senescent microglia prior to cell transplantation.
2025-11-24 | GSE252236 | GEO
Project description:A Trisomy 21-Associated Hotspot CSF2RB Mutation in Human Microglia Confers Resilience to Alzheimer’s Disease
| PRJNA1058989 | ENA
Project description:A Trisomy 21-Associated Hotspot CSF2RB Mutation in Human Microglia Confers Resilience to Alzheimer’s Disease [WGS]
| PRJNA1181027 | ENA
Project description:A Trisomy 21-Associated Hotspot CSF2RB Mutation in Human Microglia Confers Resilience to Alzheimer’s Disease (scRNA-Seq)
| PRJNA1058992 | ENA
Project description:A Trisomy 21-Associated Hotspot CSF2RB Mutation in Human Microglia Confers Resilience to Alzheimer’s Disease (bulk RNA-Seq)
| PRJNA1058988 | ENA
Project description:Down's syndrome (DS; also known as trisomy 21; T21) is caused by a triplication of all or part of human chromosome 21 (chr21). DS is the most common genetic cause of intellectual disability attributable to a naturally-occurring imbalance in gene dosage. DS incurs huge medical, healthcare, and socioeconomic costs, and there are as yet no effective treatments for this incapacitating human neurogenetic disorder. There is a remarkably wide variability in the 'phenotypic spectrum' associated with DS; the progression of symptoms and the age of DS onset fluctuate, and there is further variability in the biophysical nature of the chr21 duplication. Besides the cognitive disruptions and dementia in DS patients other serious health problems such as atherosclerosis, altered lipogenesis, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), autoimmune disease, various cancers including lymphoma, leukemia, glioma and glioblastoma, status epilepticus, congenital heart disease, hypotonia, manic depression, prostate cancer, Usher syndrome, motor disorders, Hirschsprung disease, and various physical anomalies such as early aging occur at elevated frequencies, and all are part of the DS 'phenotypic spectrum.' This communication will review the genetic link between these fore-mentioned diseases and a small group of just five stress-associated microRNAs (miRNAs)-that include let-7c, miRNA-99a, miRNA-125b, miRNA-155, and miRNA-802-encoded and clustered on the long arm of human chr21 and spanning the chr21q21.1-chr21q21.3 region.
| S-EPMC5756687 | biostudies-literature
Project description:Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modelled this leukemic evolution through stepwise gene editing of GATA1s, SMC3+/- and MPLW515K providing 20 different trisomy or disomy 21 iPSC clones. The CD41+/CD42+ MK were sorted (10 000 to 30 000 cells) and submitted to cell lysis, transposition, and purification steps. The transposed DNA fragments were amplified by PCR 12 times using adapters from the Nextera Index Kit (Illumina). PCR purification was performed using MinElute PCR Purification Kit (Qiagen, 28004) to remove large fragments and remaining primers. Library quality was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies 5067-4626). Libraries were sequenced using NovaSeq-6000 sequencer (Illumina; 50 bp paired-end reads).
2022-06-15 | E-MTAB-11044 | biostudies-arrayexpress
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