Similar Datasets
Project description:Murine N9 microglial cells were treated with LPS (1µg/ml) for 6 hours. Comparing LPS treated vs. untreated microglial cells will expand upon our previous study comparing the microgial transcriptional reponse from wild-type vs. 5XFAD mice in an effort to further understand the transcriptional response in Alzheimer's disease progression
2021-09-01 | GSE183038 | GEO
Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4
2015-11-04 | E-GEOD-74614 | biostudies-arrayexpress
Project description:Several genetic risk factors for Alzheimer’s Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aβ (fAβ) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.
2024-02-01 | GSE254205 | GEO
Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.
2018-09-18 | PXD009137 | Pride
Project description:Microglial endolysosomal dysfunction is strongly implicated in neurodegeneration. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimer’s Disease (AD) models and in human AD brain, and that the onset of this state is emphasised in females. Cst7 (Cystatin F) is among the most highly unregulated genes in these microglia. However, the sex-specific function of Cst7 in neurodegenerative disease is not understood. Here, we crossed Cst7 -/- mice with the App NL-G-F mouse to test the role of Cst7 in a model of amyloid-driven AD.
2023-11-22 | E-MTAB-13360 | biostudies-arrayexpress
Project description:Filamentous fungi are ubiquitous organisms and major plant biomass degraders. As a single colony, some fungal species can colonize large areas as up to five soccer stadia. During growth, the mycelium encounters heterogeneous carbon sources. Here we assessed whether substrate heterogeneity is a main determinant of spatial gene expression in colonies of Aspergillus niger. This question was addressed by analyzing whole-genome gene expression in five concentric zones of 5-day-old sugar beet pulp grown colonies. Growth, protein production and secretion were occurring throughout the whole colony. Carbon and nitrate utilization were constant from the centre to the periphery whereas genes encoding plant cell wall degrading enzymes were expressed with a different pattern across the colony. Finally our results demonstrate a fine-tuning of the different enzymatic tools available in A. niger and expand the knowledge on how this fungus adapts as it colonizes complex environments.
2016-03-04 | GSE66641 | GEO
Project description:Microglia are strongly implicated in the development and progression of Alzheimer’s disease (AD), yet the precise mechanisms underlying their effects on neuropathology remain unclear. To further define the influence of microglia on AD neuropathology, we generated a novel mouse model of AD that genetically lack microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA) that is further accompanied by transcriptional changes within multiple cell types, a dramatic induction of brain calcification and cerebral hemorrhages, and premature lethality. Importantly, adult microglia replacement fully rescues these comorbidities, supporting novel roles for microglia in maintaining vascular function and preventing brain calcification. We further examined the clinical implications of these findings in human tissue and hiPSC-derived microglia, finding evidence that calcification is inversely related to plaque pathology and that microglial interactions with calcifications are altered by genetic AD risk factors.
2021-11-24 | GSE189033 | GEO
Project description:An imbalance in thyroid hormones (THs) is associated with reversible dementia and Alzheimer’s disease (AD) pathogenesis. Whether hypothyroidism occurs in AD brains and how it affects AD pathology remain largely unknown. Here, we find that reduced conversion of thyroxine (T4) to tri-iodothyronine (T3) in the brain by decreased iodothyronine deiodinase 2 (DIO2) leads to hippocampal hypothyroidism in early AD model mice prior to TH changes in the blood. A TH deficiency causes immune tolerance with decreased phagocytic activity in microglia, thereby aggravating AD pathology. We demonstrate that microglial ecto-5’-nucleotidase (CD73) is reduced in the hypothyroid state and that its inhibition contributes to immune tolerance in microglia. Thus, our data define a molecular mechanism through which decreased conversion of T4 to T3 in the early AD brain, and consequent brain hypothyroidism causes microglial dysfunction and exacerbates AD pathology.
2023-09-01 | GSE219130 | GEO
Project description:An imbalance in thyroid hormones (THs) is associated with reversible dementia and Alzheimer’s disease (AD) pathogenesis. Whether hypothyroidism occurs in AD brains and how it affects AD pathology remain largely unknown. Here, we find that reduced conversion of thyroxine (T4) to tri-iodothyronine (T3) in the brain by decreased iodothyronine deiodinase 2 (DIO2) leads to hippocampal hypothyroidism in early AD model mice prior to TH changes in the blood. A TH deficiency causes immune tolerance with decreased phagocytic activity in microglia, thereby aggravating AD pathology. We demonstrate that microglial ecto-5’-nucleotidase (CD73) is reduced in the hypothyroid state and that its inhibition contributes to immune tolerance in microglia. Thus, our data define a molecular mechanism through which decreased conversion of T4 to T3 in the early AD brain, and consequent brain hypothyroidism causes microglial dysfunction and exacerbates AD pathology.
2023-09-01 | GSE219129 | GEO
Project description:APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD) with increased odds ratios in females. Targeting amyloid plaques show modest improvement in male non-APOE4 carriers. Leveraging single cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female AD patients, we identify a new subset of neutrophils, interacting with microglia associated with cognitive impairment. This phenotype is defined by increased IL-17 and IL-1 co-expressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE e4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFb, and immune checkpoints including LAG-3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored microglial response to neurodegeneration (MGnD), limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of MGnD phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE e4 female carriers with cognitive impairment.
2024-06-04 | GSE262632 | GEO