Similar Datasets
Project description:Gamma entrainment binds higher order brain regions and alleviates neurodegeneration
| PRJNA474231 | ENA
Project description: Not available
| S-EPMC6697125 | biostudies-literature
Project description:DNA double strand breaks (DSBs) are linked to neurodegeneration and senescence. However, it is not clear how DSB-bearing neurons influence neuroinflammation associated with neurodegeneration. Here, we characterize DSB-bearing neurons from the CK-p25 mouse model of neurodegeneration using single-nucleus, bulk, and spatial transcriptomic techniques. DSB-bearing neurons enter a late-stage DNA damage response marked by NFκB-activated senescent and antiviral immune pathways. In humans, Alzheimer’s disease pathology is significantly associated with immune activation in excitatory neurons. Spatial transcriptomics reveal that regions of CK-p25 brain tissue dense with DSB-bearing neurons harbor signatures of inflammatory microglia, which is ameliorated by NFκB knock-down in neurons. Inhibition of NFκB in DSB-bearing neurons also reduces microglia activation in organotypic mouse brain slice culture. In conclusion, DSBs activate immune pathways in neurons, which in turn adopt a senescence-associated secretory phenotype to elicit microglia activation. These findings highlight a novel role for neurons in the mechanism of disease-associated neuroinflammation.
2022-05-10 | GSE174265 | GEO
Project description:To explore whether tau-related epigenomic changes that we found human brain H3K9ac data (Synapse ID: syn4896408) are recapitulated in mouse models known to accumulate tau, we generated hippocampal H3K9ac ChIP-seq profiles from two different mouse models each at an early and a late stage of neurodegeneration. Specifically, we studied 6 and 11 months old mutant tau mice (MAPT P301S), which start to accumulate phosphorylated tau in neurons by 6 months. Wild-type mice of the same age were used as controls. The second mouse model was the CK-p25 model, which is characterized by increased amyloid-β levels early after p25 induction followed by increased tau phosphorylation and neuronal loss at later stages. Three months old CK-p25 mice were studied 2 weeks and 6 weeks after p25 induction and compared with CK littermate controls.
2018-12-07 | GSE97560 | GEO
Project description:Transcriptome Changes of CK-p25 Mice
| PRJNA235922 | ENA
Project description:In this study, we used single-cell RNA-sequencing to gain unprecedented insight into the phenotypic heterogeneity and the transcriptional dynamics of microglia cells during the progression of neurodegeneration. Briefly, by using a severe neurodegeneration mouse model with Alzheimer’s-like pathology and phenotypes (CK-p25 model), we surveyed microglia activation by RNA sequencing longitudinally at fine temporal- and single-cell resolution. In summary, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered novel microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs. These insights into the molecular programs underlying microglia activation provided by our study may pave the way for designing new rational and efficient strategies to treat Alzheimer’s and other neurodegenerative diseases.
2017-10-10 | GSE103334 | GEO
Project description:Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive decline of cognitive ability. An important component of AD, and other chronic neurodegenerative diseases, is generation of an innate inflammatory response within the CNS, characterized by activation of microglia, the resident immune cells of the brain. Transcription factor PU.1 has been known to play an important role in myeloid and lymphoid cell development, however its function in microglia and how it contributes to disease pathology is not well understood. Using transcriptional and chromatin state profiles during AD-like pathology in the CK-p25 mouse model of neurodegeneration, we showed that PU.1 specifically targets noncoding regions which regulate expression changes of immune response genes during AD, suggesting it may act as master regulator of microglia activation. Here, we examine the role of PU.1 in neurodegeneration by using a conditional knockout (cKO) cassette (Cx3cr1CreER+/-) to inducibly deplete PU.1 from microglia in the CK-p25 mouse model of neurodegeneration. We found that knocking out PU.1 rescues multiple neurodegenerative phenotypes. Specifically, PU.1 inhibition reduces neurodegeneration-specific increase in microglia cell number, improves neuronal survival and reverses functional synaptic plasticity deficits in the hippocampus of the CK-p25 mouse.
2021-01-01 | GSE117868 | GEO
Project description:Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer’s Disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq in human post-mortem prefrontal cortex samples and found that excitatory neurons in AD were enriched for somatic mosaic gene fusions. Gene fusions were particularly enriched in excitatory neurons with DNA damage repair and senescence gene signatures. In addition, somatic genome structural variations and gene fusions were enriched in neurons burdened with DSBs in the CK-p25 mouse model of neurodegeneration. Neurons enriched for DSBs also had elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic, neuronal development, and histone genes. Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.
2023-09-27 | GSE227438 | GEO
Project description:Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer’s Disease (AD) with the potential to disrupt genome integrity. We show increased mosaic structural variations and gene fusions in neurons burdened with DSBs in the CK-p25 inducible mouse model of neurodegeneration. Next, we used full-transcript single-nucleus RNA-seq across 47 human post-mortem prefrontal cortex and find that excitatory neurons in AD are enriched for mosaic gene fusions. In addition, gene fusions are particularly enriched in excitatory neurons with senescence and DNA repair gene signatures. Neurons enriched for DSBs also have elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic and neuronal development genes. Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.
2023-09-27 | GSE227444 | GEO
Project description:Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer’s Disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq in human post-mortem prefrontal cortex samples and found that excitatory neurons in AD were enriched for somatic mosaic gene fusions. Gene fusions were particularly enriched in excitatory neurons with DNA damage repair and senescence gene signatures. In addition, somatic genome structural variations and gene fusions were enriched in neurons burdened with DSBs in the CK-p25 mouse model of neurodegeneration. Neurons enriched for DSBs also had elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic, neuronal development, and histone genes. Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.
2023-09-27 | GSE227443 | GEO