INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model
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ABSTRACT:
PROVIDER: PRJNA723566 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14294888_1.fastq.gz | Fastqsanger.gz | |||
| SRR14294888_2.fastq.gz | Fastqsanger.gz | |||
| SRR14294889_1.fastq.gz | Fastqsanger.gz | |||
| SRR14294889_2.fastq.gz | Fastqsanger.gz | |||
| SRR14294890_1.fastq.gz | Fastqsanger.gz |
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Project description:We crossed Tyrobp-deficient and Inpp5d-deficient mice with App(NL-G-F/NL-G-F) Alzheimer model mice (hereafter, NLGF) and generate Tyrobp-/-;Inpp5d+/-;NLGF mice to assess the role of Inpp5d in Tyrobp-/- mice. We isolated microglia from NLGF, Tyrobp-/-;NLGF, and Tyrobp-/-;Inpp5d+/-;NLGF mice and analyzed microglial transcriptome using RNA-sequencing. Tyrobp-/- microglia showed substantially different transcriptome compared with NLGF microglia. Previously described "disease asscociated microglia" genes were enriched in the differentially expressed genes in Tyrobp-/- microglia. On the other hand, Tyrobp-/-;Inpp5d+/-;NLGF microglia showed similar transcriptome to Tyrobp-/- microglia except several genes (e.g., Wdfy1, Mamdc2, Klrb1f). These data suggest Inpp5d modulates microglial functions without affecting disease associated microglial gene expression in Tyrobp-/-;NLGF micrglia.
2023-02-24 | GSE172499 | GEO
Project description:The genetic associations of TREM2 loss-of-function variants with Alzheimer disease (AD) indicate the protective roles of microglia in AD pathogenesis. Functional deficiencies of TREM2 disrupt microglial clustering around amyloid β (Aβ) plaques, impair their transcriptional response to Aβ, and worsen neuritic dystrophy. However, the molecular mechanism underlying these phenotypes remains unclear. In this study, we investigated the pathological role of another AD risk gene, INPP5D, encoding a phosphoinositide PI(3,4,5)P3 phosphatase expressed in microglia. In a Tyrobp-deficient TREM2 loss-of-function mouse model, Inpp5d haplodeficiency restored the association of microglia with Aβ plaques, partially restored plaque compaction, and astrogliosis, and reduced phosphorylated tau+ dystrophic neurites. Mechanistic analyses suggest that TREM2/TYROBP and INPP5D exert opposing effects on PI(3,4,5)P3 signaling pathways as well as on phosphoproteins involved in the actin assembly. Our results suggest that INPP5D acts downstream of TREM2/TYROBP to regulate the microglial barrier against Aβ toxicity, thereby modulates Aβ-dependent pathological conversion of tau.
| S-EPMC10074152 | biostudies-literature
Project description:INTRODUCTION: INPP5D is genetically associated with Alzheimer’s disease risk. Loss of Inpp5d alters amyloid pathology in models of amyloidosis. Inpp5d is predominantly expressed in microglia but its function in brain is poorly understood. METHODS: We performed single-cell RNA-sequencing to study the effect of Inpp5d loss on wild-type mouse brain transcriptomes. RESULTS: Loss of Inpp5d has sex-specific effects on the brain transcriptome. Affected genes are enriched for multiple neurodegeneration terms. Network analyses reveal a gene co-expression module centered around Inpp5d in female mice. Inpp5d loss alters PTN, PSAP, and VEGFA signaling probability between cell types. DISCUSSION: Our data suggest Inpp5d’s normal function is entangled with mechanisms involved in neurodegeneration. We report the effect of Inpp5d loss without pathology and show that this has dramatic effects on gene expression. Our study provides a critical reference for researchers of neurodegeneration, allowing separation of disease-specific changes mediated by Inpp5d in disease from baseline effects of Inpp5d loss.
2024-06-26 | GSE254999 | GEO
Project description:Microglia and monocyte-derived macrophages (MDM) are key players in coping with Alzheimer's disease (AD). In amyloidosis mouse models, activation of microglia was found to be TREM2-dependent. Here, using Trem2-/-5xFAD mice, we assessed whether MDM act via a TREM2-dependent pathway. We adopted a treatment protocol targeting the programmed cell death ligand-1 (PD-L1) immune checkpoint, previously shown to modify AD via MDM involvement. Blocking PD-L1 in Trem2-/-5xFAD mice resulted in cognitive improvement and reduced levels of water-soluble amyloid beta (Aβ)1-42 with no effect on amyloid plaque burden. Single-cell RNA sequencing revealed that MDM, derived from both Trem2-/- and Trem2+/+5xFAD mouse brains, express a unique set of genes encoding scavenger receptors (e.g. Mrc1, Msr1). Blocking monocytes trafficking using anti-CCR2 antibody completely abrogated the cognitive improvement induced by anti-PD-L1 in Trem2-/-5xFAD mice, and similarly but to lower extent in Trem2+/+5xFAD mice. These results highlight a TREM2-independent disease-modifying activity of MDM in amyloidosis mouse model.
2021-10-24 | GSE176085 | GEO
Project description:Microglia and neuroinflammation are implicated in the development and progression of Alzheimer’s disease (AD). To better understand microglia-mediated processes in AD, we studied the function of INPP5D/SHIP1, a gene linked to AD through GWAS. Immunostaining and single nucleus RNA sequencing confirmed that INPP5D expression in the adult human brain is enriched in microglia. Examination of prefrontal cortex across a large cohort revealed reduced full-length soluble INPP5D protein levels in AD patient brains compared to cognitively normal controls. However, elevated INPP5D immunostaining in microglia in the AD brain was observed, which was driven by elevations in plaque-associated microglia suggesting that these two methods quantify different pools of INPP5D. Examination of INPP5D overexpression and bi-allelic loss-of-function in induced pluripotent stem cell derived microglia (iMGs) revealed that INPP5D LOF most closely resemble microglia in the AD brain with respect to immune signaling alterations, supporting the hypothesis that INPP5D function is reduced in AD microglia. The functional consequences of reduced INPP5D activity were evaluated in human iMGs, using both pharmacological inhibition of the phosphatase activity of INPP5D and genetic reduction in copy number. Unbiased transcriptional and proteomic profiling of these iMGs suggested an upregulation of innate immune signaling pathways, lower levels of scavenger receptors, reduced lysosomal proteins and altered inflammasome signaling with INPP5D reduction. INPP5D inhibition induced the secretion of IL-1ß and IL-18, further implicating inflammasome activation. Inflammasome activation was confirmed through visualization of inflammasome formation through ASC immunostaining in INPP5D-inhibited iMGs, increased cleaved caspase-1 and through rescue of elevated IL-1ß and IL-18 with caspase-1 and NLRP3 inhibitors. In accord, lower INPP5D is associated with higher IL-18 levels and an elevation in microglia with ASC specks in the AD brain. This work implicates INPP5D as a regulator of inflammasome signaling in human microglia.
2023-09-27 | GSE244209 | GEO
Project description:Microglia and neuroinflammation play an important role in the development and progression of Alzheimer’s disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in INPP5D-disrupted iPSC-derived human microglia, we find that reduction in INPP5D activity is associated with molecular profiles consistent with disrupted autophagy and inflammasome activation. These findings are validated through targeted pharmacological experiments which demonstrate that reduced INPP5D activity induces the formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1 and IL-18. Further, in-depth analyses of human brain tissue across hundreds of individuals using a multi-analytic approach provides evidence that a reduction in function of INPP5D in microglia results in inflammasome activation in AD. These findings provide insights into the molecular mechanisms underlying microglia-mediated processes in AD and highlight the inflammasome as a potential therapeutic target for modulating INPP5D-mediated vulnerability to AD.
2024-01-26 | PXD046040 | Pride
Project description:Alzheimer's disease (AD) is the most common form of dementia, characterized by accumulation of amyloid beta (Abeta) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Abeta pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App (NL-G-F/NL-G-F) and 3xTg-AD-H mouse models. Genes commonly altered in App (NL-G-F/NL-G-F) and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App (NL-G-F/NL-G-F) cortex as Abeta amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App (NL-G-F/NL-G-F) cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Abeta amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD.
2017-12-21 | GSE92926 | GEO
Project description:Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer’s disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed TYROBP as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both TREM2 and TYROBP. In this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2 and TYROBP by integrating signatures from transgenic Drosophila models of AD and transcriptome-wide gene co-expression networks from two human AD cohorts.
2018-03-07 | GSE99012 | GEO
Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),
2015-07-06 | E-GEOD-70475 | biostudies-arrayexpress
Project description:TREM2 is a microglial cell surface receptor, with risk mutations linked to Alzheimer’s disease (AD), including R47H. TREM2 signalling via SYK aids phagocytosis, chemotaxis, survival, and changes to microglial activation state. In AD mouse models, knockout (KO) of TREM2 impairs microglial clustering around amyloid, and prevents microglial activation. The R47H mutation is proposed to reduce TREM2 ligand binding. We investigated cell phenotypes of the R47H mutant and TREM2 KO in a model of human microglia, and compared their transcriptional signatures, to determine the mechanism by which R47H TREM2 disrupts function. We generated human microglia-like iPSC-macrophages (pMac) from isogenic induced pluripotent stem cell (iPSC) lines, with homozygous R47H mutation or TREM2 knockout (KO). We firstly validated the effect of the R47H mutant on TREM2 surface and subcellular localization in pMac. To assess microglial phenotypic function we measured phagocytosis of dead neurons, cell morphology, directed migration, survival, and LPS-induced inflammation. We performed bulk RNA-seq, comparing significant differentially-expressed genes (DEGs: p<0.05) between the R47H and KO versus WT, and bioinformatically predicted potential upstream regulators of TREM2-mediated gene expression. Altered gene expression in the R47H TREM2 pMac overlapped by 90% with the TREM2 KO, and was characterized by dysregulation of genes involved with immunity, proliferation, activation, chemotaxis and adhesion. Downregulated mediators of ECM adhesion included the vitronectin receptor αVβ3, and consequently R47H TREM2 pMac adhered weakly to vitronectin compared with WT pMac. To counteract these transcriptional defects, we investigated TGFβ1, as a candidate upstream regulator. TGFβ1 failed to rescue vitronectin adhesion of pMac, although improved αVβ3 expression. The R47H mutation is not sufficient to cause gross phenotypic defects of human pMac under standard culture conditions. However, overlapping transcriptional defects with TREM2 KO supports the hypothesised partial loss-of-function effects of the R47H mutation. Furthermore, transcriptomics can guide us to more subtle phenotypic defects in the R47H cells, such as reduced cell adhesion, and can be used to predict targets for therapeutic intervention.
2020-11-24 | GSE157635 | GEO