SYK coordinates neuroprotective microglial responses in neurodegenerative disease [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA874948 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21315006_1.fastq.gz | Fastqsanger.gz | |||
| SRR21315006_2.fastq.gz | Fastqsanger.gz | |||
| SRR21315007_1.fastq.gz | Fastqsanger.gz | |||
| SRR21315007_2.fastq.gz | Fastqsanger.gz | |||
| SRR21315008_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 128 |
Similar Datasets
Project description:SYK coordinates neuroprotective microglial responses in neurodegenerative disease
| PRJNA874943 | ENA
Project description:Many neurodegenerative diseases are thought to be caused by impaired containment and/or disposal of neurotoxic material such as amyloid beta (Ab) and myelin debris. Indeed, recent human genome-wide association studies (GWAS) and animal model studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, as well as various innate immune receptors expressed by microglia in the control of neurotoxic material and subsequent neurodegenerative disease pathogenesis. Yet, the critical intracellular molecules that orchestrate the neuroprotective functions of microglia in degenerative disorders remain poorly understood. In our studies, we have identified the innate immune signaling molecule spleen tyrosine kinase (SYK) as a key regulator of microglial phagocytosis in neurodegenerative disease. We find that targeted deletion of SYK in microglia leads to exacerbated Ab deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Furthermore, disruption of SYK signaling in this AD model was also shown to impede the development of disease-associated microglia (DAMs), alter AKT/GSK3b-signaling in microglia, and to cause severe deficits in the ability of microglia to phagocytose Ab. Importantly, these critical neuroprotective functions of SYK in microglia were not only restricted to Ab-driven models of neurodegeneration, as we found that SYK is also a critical regulator of microglial phagocytosis and DAM phenotype acquisition in demyelinating disease. Collectively, these results help to break new ground in our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material. Moreover, these findings suggest that targeting SYK may offer a therapeutic strategy to treat a spectrum of neurodegenerative disorders.
2022-10-15 | GSE212308 | GEO
Project description:SYK coordinates neuroprotective microglial responses in neurodegenerative disease [Bulk RNA-seq]
| PRJNA874744 | ENA
Project description:Many neurodegenerative diseases are thought to be caused by impaired containment and/or disposal of neurotoxic material such as amyloid beta (Ab) and myelin debris. Indeed, recent human genome-wide association studies (GWAS) and animal model studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, as well as various innate immune receptors expressed by microglia in the control of neurotoxic material and subsequent neurodegenerative disease pathogenesis. Yet, the critical intracellular molecules that orchestrate the neuroprotective functions of microglia in degenerative disorders remain poorly understood. In our studies, we have identified the innate immune signaling molecule spleen tyrosine kinase (SYK) as a key regulator of microglial phagocytosis in neurodegenerative disease. We find that targeted deletion of SYK in microglia leads to exacerbated Ab deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Furthermore, disruption of SYK signaling in this AD model was also shown to impede the development of disease-associated microglia (DAMs), alter AKT/GSK3b-signaling in microglia, and to cause severe deficits in the ability of microglia to phagocytose Ab. Importantly, these critical neuroprotective functions of SYK in microglia were not only restricted to Ab-driven models of neurodegeneration, as we found that SYK is also a critical regulator of microglial phagocytosis and DAM phenotype acquisition in demyelinating disease. Collectively, these results help to break new ground in our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material. Moreover, these findings suggest that targeting SYK may offer a therapeutic strategy to treat a spectrum of neurodegenerative disorders.
2022-10-15 | GSE212277 | GEO
Project description:Recent studies have begun to reveal critical roles for the brain's professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer's disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3β-signaling, and restrict Aβ phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aβ load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material.
| S-EPMC9617784 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-10-15 | GSE212310 | GEO
Project description:Amyloid-β (Aβ) accumulation is a hallmark of Alzheimer’s disease (AD). Emerging evidence suggests that impaired microglial Aβ phagocytosis is a key feature in AD, highlighting the therapeutic potential of enhancing this innate immune function. Here, we demonstrate that genetic deletion or pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) ameliorated memory deficits and reduced Aβ burden in APP/PS1 mice. Moreover, we show that PTP1B was highly expressed in microglia, and its deficiency promoted a transcriptional shift toward immune activation and phagocytosis. Consistently, PTP1B deletion in microglia enhanced phagocytosis and metabolic fitness, supported by increased AKT-mTOR signaling, a pathway essential for meeting the energy demands of activation. Mechanistically, we identified spleen tyrosine kinase (SYK), a key regulator of microglial phagocytosis, as a direct substrate of PTP1B. Inhibition of SYK showed that PTP1B modulates microglial activation in a SYK-dependent manner. These findings established PTP1B as a critical modulator of microglial activation and a potential therapeutic target for AD.
2026-02-02 | GSE315736 | GEO
Project description:Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer’s disease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature, “diseaseassociated microglia” (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK3β-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adaptor DAP10, which also binds TREM2. Thus, microglial responses to Aβ involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.
2022-10-10 | GSE195518 | GEO
Project description:PTP1B inhibition promotes microglial phagocytosis in Alzheimer's disease models by enhancing SYK signaling
| PRJNA1398868 | ENA
Project description:Hippocampal neuroinflammation (HNF) is a key pathological feature in neurodegenerative disorders. Milk-derived exosomes are bioactive extracellular vesicles, yet their potential to regulate neuroinflammatory responses in the brain remains underexplored. This study aimed to characterize the superior properties and protein composition of exosomes derived from desert milk (D-Exo), and to investigate their neuroprotective and anti-neuroinflammatory effects in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and an LPS-induced HNF mice model. Methods: Exosomes were isolated from desert and non-desert milk (ND-Exo). Balb/c mice were orally gavaged with D-Exo or 0.9% NaCl for 28 days before LPS injection. Cognitive function was assessed via behavioral tests, with microglial/astrocyte activation analyzed by immunofluorescence. BV2 microglial cells were pretreated with exosomes prior to LPS stimulation; inflammatory responses and polarization status were examined by RT-PCR. Results: D-Exo showed superior stability and was uniquely enriched with specific proteins (e.g., SIL1, FN1,FGG). These proteins are linked to HNF, blood-brain barrier (BBB) integrity, and the AMPK signaling pathway. In LPS-induced mice, D-Exo administration improved spatial learning and memory, elevated hippocampal brain-derived neurotrophic factor (BDNF) and microtubule-associated protein 2 (MAP2) levels, alleviated cognitive deficits and neuronal damage, and reduced Amyloid-beta 1-42 (Aβ1-42) and Tau accumulation. It also suppressed systemic and neuroinflammatory cytokines while attenuating microgliosis and astrogliosis. In LPS-stimulated BV2 microglia cells, D-Exo shifted microglial polarization from the M1 phenotype toward the M2 phenotype. Conclusions: D-Exo is enriched with specific proteins, attenuates neuroinflammation and cognitive deficits by regulating microglial M1/M2 polarization and AMPK pathway, highlighting its preventive potential.
2025-12-11 | PXD071863 |