A cell therapy to restore Trem2 function in a mouse model of Alzheimer's disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE235607 | GEO | 2023/06/26
REPOSITORIES: GEO
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Project description:Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer’s disease (AD). A number of mutations in the microglial protein TREM2 (triggering receptor expressed on myeloid cells 2) have been associated with increased risk for developing Alzheimer’s disease (AD), most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human iPSC-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a pro-inflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyper-responsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuron-microglia co-cultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism. These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.
2024-03-06 | GSE241858 | GEO
Project description:Microglia play important roles in maintaining brain homeostasis and neurodegeneration. The discovery of genetic variants in genes predominately or exclusively expressed in myeloid cells, factors for Alzheimer’s disease (AD) highlights the importance of microglial biology in the brain. such as Apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2), as the strongest risk factors for Alzheimer’s disease (AD) highlights the importance of microglial biology in the brain. The sequence, structure and function of several microglial proteins are poorly conserved across species, which has hampered the development of strategies aiming to modulate the expression of specific microglial genes. One way to target APOE and TREM2 is to modulate their expression using antisense oligonucleotides (ASOs). In this study, we identified selective and potent ASOs for human APOE and TREM2. We proved their efficacy in human iPSC microglia in vitro, as well as their pharmacological activity in vivo in a xenografted microglia model. We demonstrate ASOs targeting human microglia can modify their transcriptional profile and their response to amyloid-b plaques in vivo in a model of AD. This study is the first proof-of-concept that human microglial can be modulated using ASOs in a dose-dependent manner to manipulate microglia phenotypes in vivo. Since ASOs can have off-target effects, besides the expected decrease of APOE and TREM2 mRNA, this microarray was performed to determine the off-target profiles of the ASOs. iPSC derived microglia were treated with the ASOs with 1.25uM and 20uM dosages, and the compounds were incubated either 24hours or 48hours.
2024-04-24 | GSE243243 | GEO
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:The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis at the single-nuclei level from brain tissue of AD patients with the R47H mutation or the common variant (CV)-TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously-identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with R47H mutation or CV, and found that R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Akt signaling, and elevation of a subset of disease-associated microglial signatures. Pharmacological Akt inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with tau fibrils. Strikingly, in R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster, and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a novel microglial modulating strategy to treat AD.
2021-12-06 | GSE140670 | GEO
Project description:The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis at the single-nuclei level from brain tissue of AD patients with the R47H mutation or the common variant (CV)-TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously-identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with R47H mutation or CV, and found that R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Akt signaling, and elevation of a subset of disease-associated microglial signatures. Pharmacological Akt inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with tau fibrils. Strikingly, in R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster, and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a novel microglial modulating strategy to treat AD.
2021-12-06 | GSE136389 | GEO
Project description:TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer’s Disease (AD) risk. In mouse models of amyloid b (Ab) accumulation, defective TREM2 function affects microglial response to Ab plaques exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior and tempered glial inflammatory response. We further showed that a variant of AL002c has been given safely in a first-in-human phase I clinical trial and engages TREM2 based on CSF biomarkers. We conclude that AL002c is a promising candidate for AD therapy.
2020-05-13 | GSE150358 | GEO
Project description:The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). To understand its pathogenicity, we performed single-nuclei RNA-sequencing of cortical tissue from AD patients with R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status. we found that the R47H mutation is associated with cell type- and sex-specific transcriptional changes in human AD, with microglia exhibiting the most robust alterations. R47H-associated microglial subpopulations were characterized by hyperactivation of AKT, one of the signaling pathways downstream of TREM2, and enhanced inflammatory signatures. In tauopathy mouse models that carry one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, the mutation induced spatial memory deficits and exacerbated tau-mediated deficits in female mice. Similar to the human data, the disease-enhancing effects of R47H microglia were associated with robust increases in proinflammatory cytokines, Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures identified using single-cell sequencing from isolated microglia. Pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures in R47H microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating brain immune responses to treat AD.
2022-07-16 | GSE154578 | GEO
Project description:The most common form of senile dementia, Alzheimer’s disease (AD), is characterized by Aβ plaques and neurofibrillary tangles in the CNS. AD genetic studies have identified high-risk hypomorphic variants in TREM2, a myeloid cell surface receptor that enables concerted microglial responses to Aβ plaques and neuronal cell death, including proliferation, survival, clustering and phagocytosis. How TREM2 promotes these responses is not known. Here, we demonstrate that TREM2 drives mTOR signaling, which maintains high ATP levels, supports biosynthetic pathways and suppresses AMPK phosphorylation and autophagy. In vitro, TREM2-deficient macrophages undergo dramatically increased autophagy and die in response to growth factor limitation or ER stress. Excessive autophagy is also evident in microglia from Trem2-/- 5XFAD mice and in post-mortem specimens from AD patients carrying TREM2 risk variants. Metabolic derailment, autophagy and cell death can be circumvented by engaging alternative energy production pathways. Thus, restoring microglial energetic and anabolic levels may be a future therapeutic avenue for TREM2-associated neurological disease.
2017-08-15 | GSE98563 | GEO
Project description:Variations in many genes linked to sporadic Alzheimer’s disease (AD), show abundant expression in microglia, however, relationships between these genes remain largely elusive. Here, we establish isogenic human ES-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1 and TREM2 loci, and curate a comprehensive atlas comprising ATACseq, ChIPseq, RNAseq and proteomics datasets. AD-like expression signatures are observed in AD mutant SORL1 and TREM2 hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicates upregulation of APOE as a convergent pathogenic node. We also observe cross-regulatory relationships between SORL1 and TREM2, where SORL1R744X hMGLs induce TREM2 expression to enhance APOE expression. AD-associated SORL1 and TREM2 mutations also impaired hMGL Aβ uptake in an APOE-dependent manner in vitro, and attenuated Aβ uptake/clearance in mouse AD brain xenotransplants. Utilizing this modeling and analysis platform for human microglia, we provide new insight into epistatic interactions in AD genes and demonstrate convergence of microglial AD genes at the APOE locus.
2020-09-01 | GSE153657 | GEO
Project description:Variations in many genes linked to sporadic Alzheimer’s disease (AD), show abundant expression in microglia, however, relationships between these genes remain largely elusive. Here, we establish isogenic human ES-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1 and TREM2 loci, and curate a comprehensive atlas comprising ATACseq, ChIPseq, RNAseq and proteomics datasets. AD-like expression signatures are observed in AD mutant SORL1 and TREM2 hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicates upregulation of APOE as a convergent pathogenic node. We also observe cross-regulatory relationships between SORL1 and TREM2, where SORL1R744X hMGLs induce TREM2 expression to enhance APOE expression. AD-associated SORL1 and TREM2 mutations also impaired hMGL Aβ uptake in an APOE-dependent manner in vitro, and attenuated Aβ uptake/clearance in mouse AD brain xenotransplants. Utilizing this modeling and analysis platform for human microglia, we provide new insight into epistatic interactions in AD genes and demonstrate convergence of microglial AD genes at the APOE locus.
2020-09-01 | GSE153655 | GEO