Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer’s disease mouse model.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE60903 | GEO | 2017/01/09
SECONDARY ACCESSION(S): PRJNA259770
REPOSITORIES: GEO
Similar Datasets
Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from APPswe/PS1dE9 (APP/PS1) mice and wildtype littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentally reflect the initial response of microglia to Aβ.
2024-04-01 | GSE226937 | GEO
Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from APPswe/PS1dE9 (APP/PS1) mice and wildtype littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentally reflect the initial response of microglia to Aβ.
2024-04-01 | GSE226938 | GEO
Project description:Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. To determine whether IL-1β-induced plaque clearance is due to enhanced microglial phagocytosis of Aβ, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of Aβ was analyzed by flow cytometry and immunohistochemistry. We found that resident microglia (CD45loCD11b+) constituted >70% of the MX04+ cells in both control and IL-1β-treated conditions, and that <10% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, we found that IL-1β treatment did not augment the percentage of MX04+ microglia nor the quantity of Aβ internalized by individual microglia. Instead, we found that IL-1β treatment resulted in a significant increase in the total number of MX04+ microglia in the hippocampus due to IL-1β-induced proliferation. Consistent with these results, transcriptomic analyses revealed very similar gene expression profiles between MX04+ and MX04- microglia, indicating IL-1β does not drive enhanced expression of phagocytosis-related genes. By contrast, IL-1β treatment was associated with large-scale changes in the expression of genes related to proliferation, immune function and inflammation. Together, these studies demonstrate that IL-1β induces microglial proliferation and the expression of genes involved in inflammatory immune functions that may be related to Aβ clearance.
2019-05-01 | GSE113539 | GEO
Project description:To examine the regulation of microglia by N-AS-triggered SPMs, we analyzed the gene expression patterns of microglia derived from WT, APP/PS1, and N-AS-injected APP/PS1 mice using RNAseq. These results indicated that N-AS-triggered SPMs activated an anti-inflammatory, positive immune response, and enhanced the phagocytic abilities of microglia in N-AS-treated APP/PS1 mice, leading to resolution of neuroinflammation and upregulation of phagocytic microglia in this AD animal model.
2020-02-29 | GSE146133 | GEO
Project description:Immunesenescence contributes to systematic aging and participates in the pathogenesis of Alzheimer’s disease (AD). To define the potential of immune rejuvenation in AD therapy, we reconstituted the immune systems of aged APP/PS1 mice through bone marrow transplantation (BMT). Single cell RNA sequencing (ScRNA-seq) of peripheral blood mononuclear cells (PBMCs) indicated that young BMT reverse the expression of aging- and AD-related genes in multiple cell types of PBMCs. Plasma proteome profiling also indicated the reduction of the plasma level of senescence-associated secretory phenotype (SASP) proteins after young BMT. Young BMT significantly reduced central and peripheral Aβ levels, alleviated brain Aβ plaque burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the aged APP/PS1 mice. These effects occurred with the improved Aβ capacity of peripheral monocytes. Collectively, our study demonstrated that rejuvenation of immune system could decrease brain Aβ deposition and other AD-type pathologies, representing a potential therapeutic approach for AD.
2023-06-27 | GSE235527 | GEO
Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.
2024-09-30 | GSE235179 | GEO
Project description:Background Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer’s disease (AD). In vitro, microglia preferentially upregulate iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of knocking down microglial iron import gene, Slc11a2, on AD-related cognitive decline and microglial transcriptional phenotype. Methods In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1Cre-ERT2;Slc11a2flfl;APP/PS1+ or – mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b+ microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted. Results DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2KD APP/PS1 females displayed significant increases in genes Enpp2, Ttr, and iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2KD cells from APP/PS1 females also exhibited decreased expression of markers related to disease-associated microglia (DAMs), such as Apoe, Ctsb, Csf1, and Hif1α. Conclusions This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in female microglia and cognitive deficits in Slc11a2KD APP/PS1 mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.
2024-07-17 | GSE269314 | GEO
Project description:Alzheimer's disease (AD) is a severe neurodegenerative disorder. Clinical trials to identify agents to treat AD have failed, and its underlying molecular pathology and etiology remain elusive. Neuroinflammation is thought to play a key role in the progression of AD. Emerging evidence has identified lower Nicotinamide adenine dinucleotide (NAD+) levels as a major factor in neurodegeneration, especially in AD. NAD+ is an important metabolite in all human cells, as it is at the convergence of many central processes in cellular and mitochondrial maintenance, including DNA repair and mitophagy (the degradation of damaged mitochondria). Our previous work found that treatment of 3xTgAD mice with an NAD+ precursor, nicotinamide riboside (NR), can improve key AD features including tau phosphorylation and learning deficits in mice. Here we used the APP/PS1 AD mouse model to interrogate the effect of NR on neuroinflammation. Microarray analysis revealed major changes in pathways and genes associated with inflammation and the APP/PS1 mice had lower NAD+ levels than WT mice. Thus, seven months old mice were treated with NR for five months and their NAD+/NADH ratio increased. Brain neuroinflammation decreased as determined by decreased activation of astrocytes and microglia, decreased pro-inflammatory cytokines and chemokines in the brains of the APP/PS1 mice. NR decreased neuroinflammation by lowering the NLRP3 inflammasome and NF-κB pathways. NR also attenuated DNA damage and apoptosis in the AD mouse brains. NR dramatically decreased senescence in the hippocampus and cortex of AD mice, relative to controls. Recent studies suggest that cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) activation are associated with DNA damage and senescence. cGAS-STING was activated in AD mice and decreases after NR treatment. Suggesting that NR can diminish neuroinflammation and senescence through the cGAS-STING pathway. NR treatment also greatly improved cognition and synaptic function in the APP/PS1 mice. We propose that the cGAS-STING pathway should be evaluated as a potential novel therapeutic target in AD.
2021-08-25 | GSE135999 | GEO
Project description:Alzheimer’s disease (AD) is a common form of dementia characterized by amyloid plaque deposition, TAU pathology, neuroinflammation and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1) shows plaque deposition and associated neuroinflammatory responses involving both astrocytes and microglia beginning around 6 months of age. However, in our colony, TAU pathology, significant neurodegeneration and cognitive decline are not apparent in this model even at older ages. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized linear modeling (GLM), functional annotation followed by validation by immunofluorescence (IF) was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2-6 months of age).
2019-11-25 | GSE136861 | GEO
Project description:Two microglial TAM receptor tyrosine kinases - Axl and Mer - have been linked to Alzheimer’s disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer’s disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia is coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer’s disease, sIngle cell RNAseq analysis comparing wild type microglia with those with Axl and Mer deficiency reveals a similar disease state transitional program of microglia but a dampened differential expression of numerous AD siganture genes in microglia lacking TAM receptors. In line with the transcriptomic data, using two-photon microscopy, we show that genetic ablation of Axl and Mer results in microglia that are unable to normally detect, respond to, organize, or phagocytose amyloid beta plaques. These major deficits notwithstanding, and contrary to expectation, TAM-deficient APP/PS1 mice develop fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques, and that TAM-driven microglial phagocytosis does not constrain, but rather promotes, plaque development.
2021-02-25 | GSE160523 | GEO