Microglia - astrocyte cross-talk in the amyloid plaque niche of an Alzheimer's disease mouse model as revealed by spatial transcriptomics
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PROVIDER: PRJNA1099249 | ENA |
REPOSITORIES: ENA
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Project description:An emerging link between circadian clock function and neurodegeneration has indicated a critical role for the molecular clock in brain health. We previously reported that deletion of the core circadian clock gene Bmal1 abrogates clock function and induces cell-autonomous astrocyte activation. Regulation of astrocyte activation has important implications for protein aggregation, inflammation, and neuronal survival in neurodegenerative conditions such as Alzheimer's disease (AD). Here, we investigated how astrocyte activation induced by Bmal1 deletion regulates astrocyte gene expression, amyloid-beta (Aβ) plaque-associated activation, and plaque deposition. To address these questions, we crossed astrocyte-specific Bmal1 knockout mice (Aldh1l1-CreERT2;Bmal1(fl/fl), termed BMAL1 aKO), to the APP/PS1-21 and the APP(NL-G-F) models of Aβ accumulation. Transcriptomic profiling showed that BMAL1 aKO induced a unique transcriptional profile affecting genes involved in both the generation and elimination of Aβ. BMAL1 aKO mice showed exacerbated astrocyte activation around Aβ plaques and altered gene expression. However, this astrogliosis did not affect plaque accumulation or neuronal dystrophy in either model. Our results demonstrate that the striking astrocyte activation induced by Bmal1 knockout does not influence Aβ deposition, which indicates that the effect of astrocyte activation on plaque pathology in general is highly dependent on the molecular mechanism of activation.
2023-03-14 | GSE227063 | GEO
Project description:In this study, we characterize the transcriptomic alterations, cellular compositions, and signaling perturbations in the amyloid plaque niche in an AD mouse model using high-resolution spatial transcriptomics (CosMx and Stereo-seq). We discover a wide heterogeneity in the cellular composition of amyloid plaque niches, marked by an increase in microglial accumulation over time. We profile the alterations of glial cells as they are exposed to plaques, and conclude that the microglial response to plaques is consistent across different brain regions, while the astrocytic response is more heterogeneous. In turn, as the microglial density of plaque niches increases, astrocytes acquire a more neurotoxic phenotype and play a key role in inducing GABAergic signaling and decreasing glutamatergic signaling in neurons of the hippocampus. Taken together, we show that astrocytic signaling around plaque pathology is disrupted with increasing microglial density, which in turn induces an imbalance in synaptic signaling in neurons in the hippocampus.
2024-04-19 | GSE263791 | GEO
Project description:In this study, we characterize the transcriptomic alterations, cellular compositions, and signaling perturbations in the amyloid plaque niche in an AD mouse model using high-resolution spatial transcriptomics (CosMx and Stereo-seq). We discover a wide heterogeneity in the cellular composition of amyloid plaque niches, marked by an increase in microglial accumulation over time. We profile the alterations of glial cells as they are exposed to plaques, and conclude that the microglial response to plaques is consistent across different brain regions, while the astrocytic response is more heterogeneous. In turn, as the microglial density of plaque niches increases, astrocytes acquire a more neurotoxic phenotype and play a key role in inducing GABAergic signaling and decreasing glutamatergic signaling in neurons of the hippocampus. Taken together, we show that astrocytic signaling around plaque pathology is disrupted with increasing microglial density, which in turn induces an imbalance in synaptic signaling in neurons in the hippocampus.
2024-04-19 | GSE263789 | GEO
Project description:Microglia - astrocyte cross-talk in the amyloid plaque niche of an Alzheimer’s disease mouse model as revealed by spatial transcriptomics (CosMx)
| PRJNA1099253 | ENA
Project description:Treatment strategies that are efficient against established Alzheimer's disease (AD) are needed. BRICHOS is a molecular chaperone domain that prevents amyloid fibril formation and associated cellular toxicity. In this study, we treated an AD mouse model seven months after pathology onset, using intravenous administration of recombinant human (rh) Bri2 BRICHOS R221E. Two injections of rh Bri2 BRICHOS R221E per week for three months in AD mice reduced amyloid b (Ab) burden, and mitigated astro- and microgliosis, as determined by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Sequencing of RNA from cortical microglia cells showed that BRICHOS treatment normalized expression of identified plaque-induced genes in mice and humans, including clusterin and GFAP. Rh Bri2 BRICHOS R221E passed the blood-brain barrier (BBB) in age-matched wildtype mice as efficiently as in the AD mice, but then had no effect on measures of AD-like pathology, and mainly affected the expression of genes involved in cellular shape and movement. These results indicate a potential of rh Bri2 BRICHOS against advanced AD and underscore the ability of BRICHOS to target amyloid-induced pathology.
2024-09-25 | GSE263166 | GEO
Project description:In this study, we combined cell-specific laser capture and RNA-seq analysis to investigate transcriptome changes in both amyloid-ß plaque-associated and plaque-distant microglia at different stages of the disease.
2022-09-28 | GSE205048 | GEO
Project description:Microglia - astrocyte cross-talk in the amyloid plaque niche of an Alzheimer’s disease mouse model as revealed by spatial transcriptomics (Stereo-seq Spatial Transcriptomics)
| PRJNA1099247 | ENA
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:MALDI mass spectrometry imaging (MSI) enables label-free, spatially resolved analysis of a wide range of analytes in tissue sections. Quantitative analysis of MSI datasets is typically performed on single pixels or manually assigned regions of interest (ROI). However, many sparse, small objects such as Alzheimer’s disease (AD) brain deposits of amyloid peptides called plaques are neither single pixels nor ROI. Here, we propose a new approach to facilitate comparative computational evaluation of amyloid plaque-like objects by MSI: a fast PLAQUE PICKER tool that enables statistical evaluation of heterogeneous amyloid peptide composition. Comparing two AD mouse models, APP NL-G-F and APP PS1, we identified distinct heterogeneous plaque populations in the NL-G-F model, but only one class of plaques in the PS1 model. We propose quantitative metrics for the comparison of technical and biological MSI replicates.
2020-10-15 | PXD020824 | Pride
Project description:Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction. Reactive astrocytes and microglia are associated with amyloid plaques in Alzheimer's disease (AD). Yet, not much is known about the molecular alterations underlying this reactive phenotype. To get an insight into the molecular changes underlying AD induced astrocyte and microglia reactivity, we performed a transcriptional analysis on acutely isolated astrocytes and microglia from the cortex of aged controls and APPswe/PS1dE9 AD mice. As expected, both cell types acquired a proinflammatory phenotype, which confirms the validity of our approach. Interestingly, we observed that the immune alteration in astrocytes was relatively more pronounced than in microglia. Concurrently, our data reveal that astrocytes display a reduced expression of neuronal support genes and genes involved in neuronal communication. The microglia showed a reduced expression of phagocytosis and/or endocytosis genes. Co-expression analysis of a human AD expression data set and the astrocyte and microglia data sets revealed that the inflammatory changes in astrocytes were remarkably comparable in mouse and human AD, whereas the microglia changes showed less similarity. Based on these findings we argue that chronically proinflammatory astrocyte and microglia phenotypes, showing a reduction of genes involved in neuronal support and neuronal signaling, are likely to contribute to the neuronal dysfunction and cognitive decline in AD. 2 cell types from 2 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-74615 | biostudies-arrayexpress