The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology
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ABSTRACT:
PROVIDER: PRJNA858001 | ENA |
REPOSITORIES: ENA
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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:In Alzheimer's disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. Although extrinsic signals, including interleukin-33 (IL-33), can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor 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.
| S-EPMC10570140 | biostudies-literature
Project description:This experiment aims at comparing the transcriptomic profiles of two subpopulations of fetal human cardiac fibroblasts (HCF) defined by their relative expression of VCAM1. VCAM1-positive and VCAM1-negative populations were isolated from commercial fetal HCF by MACS against VCAM1. The RNA-seq procedure was outsourced to GENEWIZ (South Plainfield, NJ, USA), and subsequent analysis was performed in-house. Briefly, total mRNA was captured using the NEBNext Poly(A) mRNA Magnetic Isolation Module, and the library was constructed with the NEBNext Ultra RNA Library Prep Kit for Illumina. Sequencing was realized on an Illumina HiSeq 2500 System.
2020-08-08 | E-MTAB-9161 | biostudies-arrayexpress
Project description:The major genetic risk factor for Alzheimer’s disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.
2024-10-04 | GSE252454 | GEO
Project description:RNA-seq of VCAM1-positive cardiac fibroblasts (VCF) and VCAM1-negative cardiac fibroblasts (VNCF).
| PRJEB38639 | ENA
Project description:we analyzed proteomics data from ApoE-/- and CD57BL/6J mouse models of Ang II-induced AAA and control mice, which were analyzed abdominal aortic tissues by LC–MS/MS.
2022-05-24 | PXD034043 |
Project description:Transcriptome outcome of rat oligodendrocyte precursor cells, which were knocked down with short-hairpin RNA (shRNA) for vascular cell adhesion molecule 1 (VCAM1)
2016-10-14 | GSE86862 | GEO
Project description:Chemotaxis is used by free-living motile bacteria to swim towards nutrient sources or away from repellents, and to navigate the environment to locate niches optimal for growth and survival. Multiple chemotaxis systems have been identified in different bacterial species, including Azospirillum brasilense. In A. brasilense, chemotaxis is mediated by two distinct chemotaxis pathways, named Che1 and Che4, that physically interact to form mixed chemotaxis signaling arrays. Signaling from the Che1 and Che4 pathways control transient increases in swimming speed and swimming reversals, respectively, during chemotaxis. In A. brasilense, chemotaxis is tightly linked to energy metabolism with this coupling occurring through the sensory input of several energy-sensing chemoreceptors and through the control of chemoreceptor activity by the c-di-GMP second messenger. Previous work has demonstrated that chemotaxis in A. brasilense also affects unrelated cellular functions including cell-to-cell clumping and flocculation. However, the molecular mechanism for these effects is not known. Here, we identify additional effects of mutations abolishing Che1 (cheA1 mutant), Che4 (cheA4 mutant) or both Che1 and Che4 (cheA1/cheA4 mutant) function on nitrogen and carbon metabolism and use whole cell proteome and metabolome mass spectrometry to further characterize the interplay between chemotaxis and metabolism. We found that CheA1 mediates most changes in chemoreceptor arrays composition and also affects small molecules signaling while a mutant lacking CheA4 displays changes in nitrogen metabolism, including nitrate assimilation and nitrogen fixation. In contrast, the mutant lacking both CheA1 and CheA4, which lacks chemotaxis and does not form chemotaxis signaling arrays, displays distinct and non-overlapping changes that suggest the assembly of chemotaxis signaling arrays modulates energy and carbon metabolism. Together, the results suggest distinct roles for CheA1, CheA4 and chemotaxis signaling arrays in modulating chemotaxis and metabolism, likely through control of distinct global regulatory networks.
2020-08-25 | MSV000086008 | MassIVE
Project description:Endothelial cells (ECs) act as an internal barrier to the vessel wall, hindering the development of inflammation, and only when activated will promote the development of vascular inflammation. However, the heterogeneity of the aortic ECs in the setting of vascular inflammation have not been fully assessed. Here, we defined 4 EC subpopulations, including Cd36+ EC, Notch3+ EC, Vcam1+ EC and Lyve1+ EC. Based on the enrichment analysis, Vcam1+ EC were considered to be a subpopulation of ECs susceptible to activation. After high-fat diet (HFD) intake, decreased expression of Krüppel-like factor 2 (Klf2) occurred only in Vcam1+ EC. Moreover, S1pr1 was validated as a downstream target protein of klf2. Upregulation of Klf2 expression ameliorated vascular ECs inflammation under HFD condition. Our study elucidates the Klf2 in Vcam1+ EC is a critical regulator of vascular inflammation and increases understanding of development and progression of aortic inflammatory disease.
2024-01-01 | GSE214014 | GEO
Project description:APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia
| PRJNA1060678 | ENA