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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE183050 | GEO | 2021/09/30

REPOSITORIES: GEO

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

Project description: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.

2018-02-15 | GSE109906 | GEO

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

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

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)

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Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice

Project description:Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that is influenced by genetic and environmental risk factors, such as inheritance of ε4 allele of APOE (APOE4), sex and diet. Here, we examined the effect of high fat diet (HFD) on amyloid pathology and expression profile in brains of AD model mice expressing human APOE isoforms (APP/E3 and APP/E4 mice). APP/E3 and APP/E4 mice were fed HFD or Normal diet for 3 months. We found that HFD significantly increased amyloid plaques in male and female APP/E4, but not in APP/E3 mice. To identify differentially expressed genes and gene-networks correlated to diet, APOE isoform and sex, we performed RNA sequencing and applied Weighted Gene Co-expression Network Analysis. We determined that the immune response network with major hubs Tyrobp/DAP12, Csf1r, Tlr2, C1qc and Laptm5 correlated significantly and positively to the phenotype of female APP/E4-HFD mice. Correspondingly, we found that in female APP/E4-HFD mice, microglia coverage around plaques, particularly of larger size, was significantly reduced. This suggests altered containment of the plaque growth and sex-dependent vulnerability in response to diet. The results of our study show concurrent impact of diet, APOE isoform and sex on the brain transcriptome and AD-like phenotype.

2018-01-13 | GSE109152 | GEO

Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation

Project description:Alzheimer’s disease (AD) is characterized by neuroinflammation, accumulation of amyloid-β (Aβ) plaques and neuronal degeneration in the brain. The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late-onset AD. ApoE interacts with complement regulator factor H (FH) but the role of this interaction in AD pathogenesis is unknown.

2023-05-03 | GSE193513 | GEO

SnRNA-seq analysis of hippocampus in TAFE3 and TAFE4 mice

Project description:The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer disease (AD). In addition to effects of apoE on amyloid-β, results have shown that apoE markedly influences pathological forms of tau and tau-mediated neurodegeneration with apoE4 having a strong deleterious effect on both parameters. In the brain, apoE is produced and secreted primarily from astrocytes and also by activated microglia though the cell-specific role of each form of apoE in the setting of neurodegeneration has not been determined. We utilized a well- characterized mouse model of tauopathy, P301S Tau transgenic mice expressing floxed APOE-e4 or APOE-e3 alleles. We crossed these mice with Aldh1l1-CreERT2 mice and at 5.5 months of age, after the onset of tau pathology, administered tamoxifen or vehicle. We then compared mice with or without inducible knockout of astrocyte APOE at 9.5 months of age. Single nucleus RNA sequencing analysis revealed striking gene expression changes in all cell types in P301S mice with astrocytic APOE4 playing a role in modulating neuron, astrocyte, and microglial gene expression to a more homeostatic state.

2021-04-13 | GSE164507 | GEO

Peripherally-expressed apoE4 impairs brain functions and exacerbates amyloid pathogenesis by compromising cerebrovascular functions

Project description:The apolipoprotein E4 (APOE4) gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE is a lipid carrier abundantly expressed in both brain and periphery. As peripheral apoE is separated from brain apoE by the blood-brain barrier, it remains unclear whether peripheral apoE impacts brain functions and AD pathogenesis. To investigate this, we developed novel mouse models that conditionally express human APOE3 or APOE4 only in the liver with no detectable apoE in the brain. We found that liver-expressed apoE4 compromised synaptic plasticity and cognitive behaviors likely by impairing cerebrovascular functions. Remarkably, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate a pathogenic effect of peripheral apoE4, providing strong rationale for targeting peripheral apoE to treat AD.

2022-06-15 | GSE125501 | GEO

Data in support of Enhanced amyloid beta proteoform detection in an Alzheimer’s disease model by integrated matrix composition enhanced MALDI Imaging and laser capture microdissection

Project description:This study has investigated several parameters to obtain increased detection of the amyloid plaque intact protein profile, including a comparison of commonly used MALDI matrices, acid based reduction of signal suppression as well as the combination of strong acid based protein aggregate extraction from laser microdissection plaques to increase detection of proteoforms. Female APPPS1-21 transgenic mice were analyzed by MALDI Imaging with different matrices on a Ultraflextreme MALDI TOF/TOF instrument followed by data analysis in SCiLS Lab software. A combination of formic acid treatment of laser capture microdissected plaques was further utilized to expand the analysis and validation of amyloid plaques.

2021-03-25 | PXD009353 | Pride

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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

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.

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