Immune Receptor Lag3 Deletion Alleviates Neurodegeneration Phenotypes in a Mouse Model of Alzheimer’s Disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE307127 | GEO | 2025/09/10
REPOSITORIES: GEO
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Project description:Microglia, resident immune cells in the brain, play a critical role in neurodevelopment and neurological diseases. We investigated the role of the immune checkpoint molecule Tim-3 (Havcr2), which was recently identified as a genetic risk factor for late-onset Alzheimer’s disease (LOAD) in microglia. While Tim-3 has been shown to play an important role in inducing T cell exhaustion, it shows high and specific expression in the microglia where its role is unknown. Here we show that Tim-3 expression in microglia was induced by TGFβ signaling. Mechanistically, Tim-3 binds both Smad2 and Tgfbr2 by its C-terminus tail and enhances TGFβ signaling by promoting the phosphorylation of Smad2 by Tgfbr, thereby contributing to microglial homeostasis. Genetic deletion of Tim-3 in microglia resulted in increased phagocytic activity with a gene expression profile skewed towards neurodegenerative microglia (MGnD) phenotype, also known as disease-associated microglia (DAM). Moreover, microglia-targeted deletion of Tim-3 ameliorated AD pathology in 5xFAD mice. Single-nucleus RNA sequencing (snRNA-seq) identified a subpopulation among MGnD/DAM microglia in Havcr2-deficient 5xFAD mice, characterized by increased pro-phagocytic and anti-inflammatory gene expression together with decreased proinflammatory gene expression. Additional single-cell RNAseq confirmed these transcriptomic shifts in Havcr2-deficient 5xFAD mice in most microglial clusters. Our study shows a Tim-3-mediated regulatory mechanism of homeostatic microglia through its interaction with TGFβ signaling and the beneficial role of targeting microglial Tim-3 in AD mice. Our findings promise a potential therapeutic strategy targeting checkpoint molecule Tim-3 in currently intractable AD.
2025-01-13 | GSE267764 | 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: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
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 | GSE140399 | GEO
Project description:In order to further understand how microglia-derived LAG3 regulates microglia homeostasis and affects the morphogenesis of astrocytes, RNA-seq was used to analyze the transcriptome changes of microglia isolated from Lag3 conditional knockout mice and littermate-born wild-type mice in P7 period. About 7000 transcripts showed the differential expression between the microglia of the corpus callosum of Lag3fl/fl and Lag3cKO-Cx3 mice, with a fold change ≥2, and a p value < 0.05. Geneontology analysis of downregulated genes were enriched in terms related to actin recombination, ciliary recombination and others, while upregulated genes are enriched in inflammatory response and other terms. These results reflected the role of microglia Lag3 in microglia development.
2024-09-30 | GSE277980 | GEO
Project description:A rare coding variant was identified within the human ABI3 gene that is associated with increased risk of Alzheimer’s disease (AD). Following this discovery, we recently demonstrated that deletion of Abi3 gene locus notably exacerbates AD neuropathology in the 5xFAD transgenic mouse model of amyloidosis. In the course of a related investigation into the functional impact of Abi3 deletion in mice, we made an unexpected discovery regarding the impact of Abi3 deletion on the non-transgenic littermates of those 5xFAD mice. In those mice, we found that deletion of Abi3 gene locus resulted in an obese phenotype. Therefore, we investigated this serendipitous discovery. In this report, we demonstrate that mice lacking Abi3 have dramatically increased body weight and body fat. Further, we determined that these mice without Abi3 have reduced energy expenditure. Additionally, we found that deletion of the Abi3 gene locus altered gene expression, particularly within immune pathways, within the hypothalamus. Subsequent immunohistological analysis of the central nervous system (CNS) revealed that microglia number and area were decreased specifically within the mediobasal hypothalamus of mice without Abi3. Altogether, this investigation establishes the functional importance of the Abi3 gene locus, particularly within the CNS, in the regulation of systemic metabolism and maintenance of healthy weight.
2022-12-13 | GSE212299 | GEO
Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.
2018-09-18 | PXD009137 | Pride
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
Project description:Background: In Alzheimer’s disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue. Methods: Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113). Results: Treatment resulted in significant reductions in amyloid-beta (Aβ) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice. Conclusions: This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.
2024-05-07 | GSE266470 | GEO
Project description:Abnormal lipid metabolism in Alzheimer’s disease (AD) was first documented by Alois Alzheimer in his early observations of patients with a then unrecognized brain disease, which he noted was characterized by a significant presence of adipose inclusions or lipoid granules. Despite this early recognition, until recently the significance of abnormal lipid metabolism in AD has been largely overlooked by the scientific community for decades, highlighting a critical gap in our understanding of this complex disease. In the past decade, numerous loci and genes with genome-wide significant evidence of affecting AD risk have been reported. Notably, a significant portion of these AD risk genes are either preferentially or exclusively expressed by microglia in the brain and/or code for enzymes that directly or indirectly regulate lipid metabolism. This suggests a major, yet uncharacterized, role of microglia in modulating brain lipid metabolism under AD pathological conditions. In our study, we dissected microglia-dependent and independent regulation of lipid metabolism in an AD-like mouse model of amyloidosis, 5xFAD, taking advantage of pharmacological and genetic interventions to eliminate microglia. Using multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL), we identified overt changes in a number of AD-associated lipids (ADALs) in postmortem patient brains and mouse models of amyloidosis. This included bis(monoacylglycerol)phosphate (BMP), a lipid class enriched in endosomal/lysosomal compartments, and the two most abundant classes of lysophospholipids: lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), which are commonly associated with inflammation. Our findings revealed that microglial depletion prevented the accumulation of arachidonic acid-containing BMP species, which are associated with lysosomal activation induced by amyloidosis via a mechanism that involves progranulin, coded by AD risk gene GRN, as shown by targeted transcriptomics, immunoblotting, and immunofluorescence. Surprisingly, AD-associated LPC and LPE accumulation was not driven by microglia. Instead, LPC accumulation correlated with astrocytic activation, while LPE accumulation seems to be associated with oxidative stress. In summary, we uncovered novel microglia-dependent and independent mechanisms that drive lipid dysregulation in AD. These findings may be mechanistically linked with the early glial lipoid deposits described by Dr. Alzheimer.
2025-08-14 | GSE278634 | GEO