Inhibition of discoidin domain receptor (DDR)-1 with nilotinib alters CSF miRNAs and is associated with reduced inflammation and vascular fibrosis in Alzheimer's Disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE279869 | GEO | 2024/10/24
REPOSITORIES: GEO
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Project description:Inhibition of discoidin domain receptor (DDR)-1 with nilotinib alters CSF miRNAs and is associated with reduced inflammation and vascular fibrosis in Alzheimer's Disease
| PRJNA1174807 | ENA
Project description:The gut microbiota and innate immune system play critical roles in Alzheimer’s disease (AD). Bacteroides is elevated in AD patients and correlates with cerebrospinal fluid levels of Aβ and tau. We found that increased amyloid-β (Aβ) plaques in Bacteroides fragilis treated APP/PS1-21 mice were associated with altered cortical expression Aβ processing genes. B. fragilis suppressed peripheral CD4+ T cell production of GM-CSF and IL-4 and transcriptional changes in microglia related to GM-CSF and IL-4 signaling, phagocytosis, and protein degradation. Furthermore, B. fragilis impaired the microglial uptake of intracranially injected Aβ42, whereas Erysipelotrichaceae strains increased uptake. Depleting murine Bacteroidetes with metronidazole decreased amyloid load in aged 5xFAD mice, increased CD4+ T cell GM-CSF production, and activated microglial pathways related to cytokine signaling, phagocytosis and lysosomal degradation. These data suggest that the gut microbiome may contribute to AD pathogenesis by suppressing peripheral cytokines and microglia phagocytic function, leading to impaired immune-mediated Aβ clearance.
2024-10-12 | GSE215438 | GEO
Project description:The gut microbiota and innate immune system play critical roles in Alzheimer’s disease (AD). Bacteroides is elevated in AD patients and correlates with cerebrospinal fluid levels of Aβ and tau. We found that increased amyloid-β (Aβ) plaques in Bacteroides fragilis treated APP/PS1-21 mice were associated with altered cortical expression Aβ processing genes. B. fragilis suppressed peripheral CD4+ T cell production of GM-CSF and IL-4 and transcriptional changes in microglia related to GM-CSF and IL-4 signaling, phagocytosis, and protein degradation. Furthermore, B. fragilis impaired the microglial uptake of intracranially injected Aβ42, whereas Erysipelotrichaceae strains increased uptake. Depleting murine Bacteroidetes with metronidazole decreased amyloid load in aged 5xFAD mice, increased CD4+ T cell GM-CSF production, and activated microglial pathways related to cytokine signaling, phagocytosis and lysosomal degradation. These data suggest that the gut microbiome may contribute to AD pathogenesis by suppressing peripheral cytokines and microglia phagocytic function, leading to impaired immune-mediated Aβ clearance.
2024-10-12 | GSE215439 | GEO
Project description:We used microarrays to detect the differences in gene-expression of wild type and Discoidin Domain Receptor 1 Tyrosine Kinase (DDR-1)-KO mice TMJ-cartilage. RNA was extracted directly of the madibular condyle cartilage
2012-01-25 | E-GEOD-35297 | biostudies-arrayexpress
Project description:The discoidin domain receptor 1 (DDR-1) deficient mice exhibit a high incidence of osteoarthritis (OA) in the temporomandibular joint (TMJ) already at early age. Young DDR-1 knock-out mice show typical histological signs of OA, like, surface fissures, loss of proteoglycans, cluster formation of the chondrocytes, altered collagen types as well as atypical arrangement of the collagen fibrils. The isolated chondrocytes from the TMJ exhibit an osteoarthritic character with high amounts of Runt-related transcription factor 2 (runx-2) and collagen type I compared to low levels of SRY (sex determining region Y)-box 9 (sox-9) and aggrecan. Especially, the amount of discoidin domain receptor 2 (DDR2) is increased, which is key player of OA in this model. The gene expression as well as the proteins of the DDR-1-deficient chondrocytes from the TMJ could be influenced by a three dimensional matrix, combined with a knockdown of runx-2 or the stimulation with components of the extracellular matrix, for example nidogen-2. These manipulations caused the osteoarthritic chondrocytes of DDR-1-deficient mice to change their gene expression towards a signature of more physiological cartilage and will open new possibilities for future regenerative treatment options of temporomandibular disorders like OA of the TMJ.
2012-01-25 | GSE35297 | GEO
Project description:Aging is a major risk factor for many neurological pathologies, including Alzheimer’s disease (AD). However, the mechanisms underlying brain aging and cognitive decline remain elusive. Body tissues are perfused by interstitial fluid (ISF), which is locally reabsorbed via the lymphatic vascular network. In contrast, the parenchyma of the central nervous system (CNS) is devoid of lymphatic vasculature; in the brain, removal of cellular debris and toxic molecules, such as amyloid beta (A) peptides, is mediated by a combination of transcellular mechanisms of transport across the blood−brain and blood−cerebrospinal fluid (CSF) barriers, phagocytosis and digestion by resident microglia and recruited monocytes/macrophages, and CSF influx and ISF efflux through a paravascular route. The recent characterization of meningeal lymphatic vessels prompted a reassessment of the conventional pathways of CNS waste clearance. The role of this vasculature in brain function, specifically in the context of aging and AD, is still poorly understood. Here we show that meningeal lymphatic vessels play an essential role in maintaining brain homeostasis by draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes. Using pharmacological, surgical, and genetic models we show that impairment of meningeal lymphatic function in adult mice slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment. Treatment with a lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance in aged mice. Disruption of meningeal lymphatic vessels in transgenic mouse models of AD promotes amyloid deposition in the meninges, which closely correlates with human meningeal pathology, and aggravates overall disease severity. Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
2018-08-03 | GSE104182 | GEO
Project description:Aging is a major risk factor for many neurological pathologies, including Alzheimer’s disease (AD). However, the mechanisms underlying brain aging and cognitive decline remain elusive. Body tissues are perfused by interstitial fluid (ISF), which is locally reabsorbed via the lymphatic vascular network. In contrast, the parenchyma of the central nervous system (CNS) is devoid of lymphatic vasculature; in the brain, removal of cellular debris and toxic molecules, such as amyloid beta (A) peptides, is mediated by a combination of transcellular mechanisms of transport across the blood−brain and blood−cerebrospinal fluid (CSF) barriers, phagocytosis and digestion by resident microglia and recruited monocytes/macrophages, and CSF influx and ISF efflux through a paravascular route. The recent characterization of meningeal lymphatic vessels prompted a reassessment of the conventional pathways of CNS waste clearance. The role of this vasculature in brain function, specifically in the context of aging and AD, is still poorly understood. Here we show that meningeal lymphatic vessels play an essential role in maintaining brain homeostasis by draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes. Using pharmacological, surgical, and genetic models we show that impairment of meningeal lymphatic function in adult mice slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment. Treatment with a lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance in aged mice. Disruption of meningeal lymphatic vessels in transgenic mouse models of AD promotes amyloid deposition in the meninges, which closely correlates with human meningeal pathology, and aggravates overall disease severity. Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
2018-08-03 | GSE113351 | GEO
Project description:Aging is a major risk factor for many neurological pathologies, including Alzheimer’s disease (AD). However, the mechanisms underlying brain aging and cognitive decline remain elusive. Body tissues are perfused by interstitial fluid (ISF), which is locally reabsorbed via the lymphatic vascular network. In contrast, the parenchyma of the central nervous system (CNS) is devoid of lymphatic vasculature; in the brain, removal of cellular debris and toxic molecules, such as amyloid beta (A) peptides, is mediated by a combination of transcellular mechanisms of transport across the blood−brain and blood−cerebrospinal fluid (CSF) barriers, phagocytosis and digestion by resident microglia and recruited monocytes/macrophages, and CSF influx and ISF efflux through a paravascular route. The recent characterization of meningeal lymphatic vessels prompted a reassessment of the conventional pathways of CNS waste clearance. The role of this vasculature in brain function, specifically in the context of aging and AD, is still poorly understood. Here we show that meningeal lymphatic vessels play an essential role in maintaining brain homeostasis by draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes. Using pharmacological, surgical, and genetic models we show that impairment of meningeal lymphatic function in adult mice slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment. Treatment with a lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance in aged mice. Disruption of meningeal lymphatic vessels in transgenic mouse models of AD promotes amyloid deposition in the meninges, which closely correlates with human meningeal pathology, and aggravates overall disease severity. Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
2018-08-03 | GSE104181 | GEO
Project description:Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which neuroinflammation plays a critical function. Recurring viral infections and loss of immune competence increase risk for developing AD, yet the cellular and molecular mechanisms driving these immune changes are unknown. Here we performed mass cytometry of peripheral blood mononuclear cells and detected an immunologic signature of AD characterized by increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. CD8+ TEMRA cells were negatively associated with cognition and single cell RNA sequencing revealed their cytotoxic effector function. Strikingly, we discovered identical, shared T cell receptors (TCRs) of clonally expanded CD8+ TEMRA cells in cerebrospinal fluid (CSF) of three AD patients. Deep TCR sequencing, machine learning, and peptide screens identified the HLA-B*08:01-restricted Epstein-Barr virus trans-activator protein BZLF1 as the cognate antigen of a novel AD CSF TCR . These results provide the first evidence of clonal, antigen-specific T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration
2019-11-04 | GSE134577 | GEO
Project description:Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which neuroinflammation plays a critical function. Recurring viral infections and loss of immune competence increase risk for developing AD, yet the cellular and molecular mechanisms driving these immune changes are unknown. Here we performed mass cytometry of peripheral blood mononuclear cells and detected an immunologic signature of AD characterized by increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. CD8+ TEMRA cells were negatively associated with cognition and single cell RNA sequencing revealed their cytotoxic effector function. Strikingly, we discovered identical, shared T cell receptors (TCRs) of clonally expanded CD8+ TEMRA cells in cerebrospinal fluid (CSF) of three AD patients. Deep TCR sequencing, machine learning, and peptide screens identified the HLA-B*08:01-restricted Epstein-Barr virus trans-activator protein BZLF1 as the cognate antigen of a novel AD CSF TCR . These results provide the first evidence of clonal, antigen-specific T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration
2019-11-04 | GSE134576 | GEO