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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE195518 | GEO | 2022/10/10

REPOSITORIES: GEO

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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

Prior activation state shapes the microglia response to anti-human TREM2 in a mouse model of Alzheimer's disease

Project description:Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer’s Disease (AD) risk is associated with the TREM2R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here we tested whether TREM2 engagement by an agonistic mAb, hT2AB, designated as a surrogate ligand facilitates microglia responses in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant (TREM2CV) or TREM2R47H. scRNA-seq of microglia from TREM2CV-5XFAD mice treated once with control IgG exposed trajectories representative of activated microglial populations including disease-associated microglia (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia. All of these were underrepresented in TREM2R47H-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia transitions. Moreover, Cyc-M and IFN-R microglia were better represented in female than male TREM2CV-5XFAD mice, likely reflecting a greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished the Cyc-M, IFN-R, and MHC-II pools in TREM2R47H-5XFAD mice. In TREM2CV-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which microglia transitions in response to Aβ had already reached their peak. Repeated treatment with a murinized version mT2AB over a 10 days period increased brain content of chemokines in TREM2R47H-5XFAD mice, consistent with microglia expansion and shifts in gene expression patterns. Thus, the impact of hT2AB on microglia responses is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation.

2020-12-08 | GSE156183 | GEO

TREM2 is a global regulator of microglia energetic and biosynthetic metabolism during steady state and in Alzheimer’s disease

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

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease [7 months]

Project description:Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor TREM2 increase AD risk and activation of “disease-associated microglia” (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene expression changes associated with AD pathology and TREM2 in 5XFAD mice and human AD by snRNA-seq. We confirmed the presence of Trem2-dependent DAM and identified a novel Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less palpable in TREM2 R47H and R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

2019-12-31 | GSE140510 | GEO

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease [15 months]

2019-12-31 | GSE140399 | GEO

Single cell RNA-seq identifies a unique microglia type associated with Alzheimer’s disease [ChIP]

Project description:Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, the roles of immune cell subsets in AD onset and progression are poorly understood. By transcriptional single cell sorting, we comprehensively map all immune populations in wild type and AD–transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify the markers, spatial-location, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices showed DAM with intracellular/phagocytic Aβ particles. Single cell analysis of DAM in Tg-AD and Trem2-/- Tg-AD revealed that the DAM program is activated in a two-step process. Activation is initiated in a Trem2 independent manner which involves down-regulation of microglia checkpoints, followed by activation of a Trem2-dependent program. These data identify a unique microglia-type, which may have important implications for future treatment of AD and other neurodegenerative diseases.

2017-06-12 | GSE98970 | GEO

Single cell RNA-seq identifies a unique microglia type associated with Alzheimer’s disease [RNA]

2017-06-12 | GSE98969 | GEO

Lack of TREM2 differentially affects the phenotype and transcriptome of mice expressing human APOE3 and APOE4

Project description:We aim to investigate the interaction between two of the major genetic risk factors for AD: inheritance of APOEε4 and deficiency of Triggering Receptor Expressed on Myeloid cells 2 (TREM2). Trem2 deletion worsened memory in AD model mice but not in their WT littermates. Interestingly, the lack Trem2 resulted in a significantly less microglia around amyloid plaques in APP mice expressing both APOE isoforms but had no impact on amyloid load. Gene expression analysis identified as Trem2 signature a cluster of highly connected immune response genes, commonly downregulated as a result of Trem2 deletion in all experimental groups, such as Clec7a, Itgax, Cts7, Mpeg1, Csf1r, Cx3cr1, Pik3cg and Spi1/PU.1. In vitro experiments with primary microglia demonstrated a decrease of Aβ phagocytosis in APOE4 versus APOE3 microglia a difference that was augmented by the absence of Trem2. Our data demonstrate that the lack of Trem2 differentially impact the phenotype and brain transcriptome of APP mice expressing human APOE isoforms probably reflecting the difference between APOE isoforms to transport lipids that can affect APOE receptor-binding properties.

2020-07-09 | GSE144125 | GEO

Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's Disease model

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

Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related Aβ pathology

Project description:Microglia are central players in Alzheimer’s Disease (AD) pathology, but analyzing microglia states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild type controls. Xenografted human microglia adopt a disease-associated (DAM) profile similar to that seen in mouse microglia, but display a more pronounced HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine CRM response to oligomeric Aβo. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other AD risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in response to AD-related pathology, which should be taken into account in translational studies.

2024-02-29 | GSE216999 | GEO

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