Antibody-mediated targeting of human microglial LILRB4 attenuates amyloid-dependent pathology
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ABSTRACT:
PROVIDER: PRJNA1065844 | ENA |
REPOSITORIES: ENA
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Project description:Microglia help limit the progression of Alzheimer’s disease (AD) by constrainingβ-Amyloid (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. LILRB4 expression and function in microglia has not been investigated. Here, we find that LILRB4 is highly expressed in microglia of patients with AD. Using mice that accumulate Aβ andcarry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia wrapping Aβ plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb)reduced Aβ load,mitigated Aβ-related behavioral abnormalities, enhanced microglia phagocytosis and attenuated expression of interferon-induced genes.In vitrobinding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction.In silicomodeling, biochemical and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.
2025-01-31 | GSE253456 | 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:APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge
| PRJNA880831 | ENA
Project description:INTRODUCTION: Gain-of-function mutations in INPP5D, which encodes for the SH2-domain-containing inositol phosphatase SHIP-1, have recently been linked to an increased risk of developing late-onset Alzheimer’s disease (LOAD). Yet, little is currently known in regards to how SHIP-1 affects neurobiology or neurodegenerative disease pathogenesis. METHODS: To bridge this knowledge gap, we generated 5xFAD Inpp5dfl/flCx3cr1Ert2Cre mice to investigate the function of microglial SHIP-1 signaling in response to amyloid beta (Aβ)-mediated pathology. RESULTS: In our studies, we found that SHIP-1 deletion in microglia leads to substantially enhanced recruitment of microglia to Aβ plaques, altered microglial gene expression, and marked improvements in neuronal health. Further, SHIP-1 loss enhanced microglial plaque containment and Aβ engulfment when compared to microglia from Cre-negative 5xFAD Inpp5dfl/fl littermate controls. DISCUSSION: These results define SHIP-1 as a pivotal regulator of microglial responses during Aβ-driven neurological disease.
2023-04-15 | GSE220279 | GEO
Project description:Background: The p38 alpha mitogen-activated protein kinase (p38a) pathway is linked to both innate and adaptive immune responses, and as such, is currently under active investigation as a target for drug development in the context of Alzheimer’s disease (AD) and other conditions with neuroinflammatory dysfunction. While preclinical data has shown that p38a inhibition can protect against AD-associated neuropathology, the underlying mechanisms are only partially elucidated. Inhibitors of p38a may provide benefit via modulation of microglial-associated neuroinflammatory responses that contribute to the development of AD pathology. The present study tests this hypothesis by knocking out microglial p38a and assessing early-stage pathological changes. Materials and methods: Conditional knockout of microglial p38a was accomplished in 5-month-old C57BL/6J wild-type and amyloidogenic AD model (APPswe/PS1dE9) mice using a tamoxifen-inducible Cre/loxP system. Beginning at 7.5 months of age, animals underwent behavioral assessment on the open field and radial arm water maze tests, followed by collection of cortical and hippocampal tissues at 11 months. Additional endpoint measures included microglial RNA-seq analysis, quantification of pro-inflammatory cytokines, assessment of amyloid burden and plaque deposition, and characterization of microglia-plaque dynamics using a combination of ELISA, immunohistochemical, and immunofluorescent techniques. Results: Loss of microglial p38a did not alter behavioral outcomes, pro-inflammatory cytokine levels, or overall amyloid plaque burden. However, this manipulation did significantly increase hippocampal levels of soluble Abeta42 and reduce colocalization of Iba1 and 6E10 in a subset microglia in close proximity to plaques, indicating that p38a suppression may alter microglial phagocytosis. Conclusion: The data presented here suggest that rather than reducing inflammation per se, the net effect of microglial p38a inhibition in the context of AD-type amyloid pathology could be an alteration of phagocytosis and/or plaque deposition. Additionally, these results support future investigations of microglial p38a signaling at different stages of disease, as well as its relationship to phagocytic processes in this particular cell-type.
2023-06-01 | GSE222257 | GEO
Project description:In Alzheimer’s disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. While extrinsic signals including interleukin-33 (IL-33) can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor(s) is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration. Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1–ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1–ApoE-dependent microglial functions ameliorates AD pathology.
2023-07-18 | GSE208006 | GEO
Project description:The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response – two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1a expression, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism.
2022-09-04 | GSE212323 | GEO
Project description:CARD9 attenuates Ab pathology and modifies microglial responses in an Alzheimer’s disease mouse model
| PRJNA973070 | ENA
Project description:APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge [Spatial transcriptomics]
| PRJNA875049 | ENA
Project description:The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response – two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1a expression, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism.
2022-09-04 | GSE212343 | GEO