Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

RNAseq of cortex of 6-month old APPPS1 and APPPS1;Apoe-/- mice

ABSTRACT: One of the hallmarks of Alzheimer’s disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-β (Aβ) peptide. ApoE influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aβ in the brain. In addition to influencing Aβ metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1∆E9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Aβ morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE109906 | GEO | 2018/02/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

RNAseq of isolated astrocytes and microglia from APPPS1E4fl/fl mice following astroycte APOE removal

Project description:The e4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease and has been shown to increase amyloid pathology relative to the presence of the e2 and e3 alleles. In the brain, apoE is primarily produced by astrocytes and under pathological conditions also by microglia. The cell-type-specific role of apoE in amyloid pathology, especially after amyloid plaque deposition, has not been fully elucidated. We generated APPPS1-21/Aldh1l1-Cre/ERT2/apoE4flox/flox and APPPS1-21/apoE4flox/flox mice. At 3.8-months-of-age, during the phase of rapid plaque growth, we administered tamoxifen to reduce astrocytic APOE4 and assessed mice at 6-months-of-age. One day before tamoxifen treatment, mice were injected with methoxy-X04, a blood-brain-barrier permeant fluorescent marker that labeled the pre-existing fibrillar amyloid plaques. By using this strategy, we were able to characterize pre-existing plaques prior to the loss of astrocytic APOE4 and to also analyze newly-formed amyloid plaques after the loss of astrocytic APOE4. Interestingly, astrocytic APOE4 deletion strongly reduced pre-existing plaques. It also prevented new plaque formation and decreased glial reactivity. Importantly, the removal of astrocytic APOE4 resulted in enhanced microglial and astrocytic phagocytic ability, which may contribute to the reduction of the amyloid pathology.

2021-09-30 | GSE183050 | GEO

The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology

Project description:In Alzheimer’s disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. While extrinsic signals including interleukin-33 (IL-33) can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor(s) is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration. Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1–ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1–ApoE-dependent microglial functions ameliorates AD pathology.

2023-07-18 | GSE208006 | GEO

Beneficial effect of ACI-24 vaccination on microglial phenotypes in an amyloidosis mouse model

Project description:Amyloid-beta (Aβ) deposition is an initiating factor in Alzheimer´s disease (AD). Microglia are the brain immune cells that surround and phagocytose Aβ, but their phagocytic capacity declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating phagocytic function. Immunotherapies are currently pursued as therapeutic strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Aβ targeting ACI-24 vaccine in preventing the AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Aβ plaque load, amyloid plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, plaque-associated microglia had the tendency to be more activated post vaccination. The lower Aβ plaque load triggered by vaccination with ACI-24 was in concordance with the bulk transcriptomic analysis that revealed a reduction in the expression of several disease-associated microglial signatures. Accordingly, plaque-distant microglia displayed a more ramified morphology, supporting beneficial effects of the vaccination on bulk microglial phenotypes. Our study demonstrates that administration of the Aβ targeting vaccine, ACI-24, triggers protective microglial responses that translate into a reduction of AD pathology suggesting its use as a safe and cost effective AD therapeutic intervention.

2023-01-09 | PXD038665 | Pride

Microglial proteomic signatures in APPPS1 and APP-KI mice

Project description:Microglial dysfunction is a key pathological feature of Alzheimer´s disease (AD), but little is known about proteome-wide changes in microglia during the course of AD pathogenesis and their consequences for microglial function. Here, we performed an in-depth proteomic characterization of microglia in two AD mouse models, the overexpression APPPS1 and the knock-in AppNL-G-F (APP-KI) model. Proteome changes were followed from pre-deposition to early, middle and advanced stages of amyloid plaque pathology, revealing a large panel of Microglial Amyloid Response Proteins (MARPs) that reflect a heterogeneity of microglial alterations triggered by Adeposition. We demonstrate that the occurrence of MARPs coincided with the deposition of fibrillar A, recruitment of microglia to amyloid plaques and phagocytic dysfunction. While the proteomic and functional microglial changes were already markedly seen in 3 months old APPPS1 mice, they were delayed in the APP-KI model that generates substantially less fibrillar A. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy.

2020-06-09 | PXD016075 | Pride

CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

Project description:Alzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia (DAM) states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of Alzheimer's disease. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.

2021-06-03 | GSE176032 | GEO

The Alzheimer’s disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta-mediated pathology [snRNA-seq]

Project description:INTRODUCTION: Gain-of-function mutations in INPP5D, which encodes for the SH2-domain-containing inositol phosphatase SHIP-1, have recently been linked to an increased risk of developing late-onset Alzheimer’s disease (LOAD). Yet, little is currently known in regards to how SHIP-1 affects neurobiology or neurodegenerative disease pathogenesis. METHODS: To bridge this knowledge gap, we generated 5xFAD Inpp5dfl/flCx3cr1Ert2Cre mice to investigate the function of microglial SHIP-1 signaling in response to amyloid beta (Aβ)-mediated pathology. RESULTS: In our studies, we found that SHIP-1 deletion in microglia leads to substantially enhanced recruitment of microglia to Aβ plaques, altered microglial gene expression, and marked improvements in neuronal health. Further, SHIP-1 loss enhanced microglial plaque containment and Aβ engulfment when compared to microglia from Cre-negative 5xFAD Inpp5dfl/fl littermate controls. DISCUSSION: These results define SHIP-1 as a pivotal regulator of microglial responses during Aβ-driven neurological disease.

2023-04-15 | GSE220279 | GEO

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)

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

Microglia - astrocyte cross-talk in the amyloid plaque niche of an Alzheimer’s disease mouse model as revealed by spatial transcriptomics (CosMx)

2024-04-19 | GSE263791 | GEO

TREM2 Drives Microglia Response to Amyloid-β via SYK-dependent and -independent Paths [DAP12KI scRNA-seq]

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 | GSE210257 | GEO

TREM2 Drives Microglia Response to Amyloid-β via SYK-dependent and -independent Paths [SYK and TREM2 scRNA-seq]

2022-10-10 | GSE195518 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data