Unveiling age-associated immune priming properties of astrocytes for trigerring microglial Aβ clearance in an APOE isoform-dependent manner [hMG_RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1148221 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Alzheimer's disease (AD)-associated allele, apolipoprotein E4 (APOE4), exhibits pathological characteristics in an age-dependent manner despite its presence from birth. The molecular and cellular changes leading to disease onset are largely unexplored. We observed using human-induced pluripotent stem cells (hiPSCs)-derived models that astrocytes acquire immune priming functions through repetitive inflammatory stimuli, with recovery periods, causing transcriptome changes similar to those in the aged brain. Astrocytic priming by amyloid-β (Aβ) promoted cytokine release, leading to enhanced microglial phagocytic activity against Aβ. Conversely, APOE4 astrocytes showed impaired priming and reduced cytokine secretion in response to Aβ, leading to decreased microglial Aβ phagocytosis. Further, using a humanized APOE knock-in mouse model, we validated the positive effect of astrocyte priming on Aβ clearance in vivo. Our findings suggest that aging astrocytes may enhance Aβ clearance through the acquisition of immune priming functions and positively regulate Aβ clearance, while APOE4 impairs this process, leading to Aβ accumulation.
2025-07-06 | GSE274870 | GEO
Project description:Alzheimer's disease (AD)-associated allele, apolipoprotein E4 (APOE4), exhibits pathological characteristics in an age-dependent manner despite its presence from birth. The molecular and cellular changes leading to disease onset are largely unexplored. We observed using human-induced pluripotent stem cells (hiPSCs)-derived models that astrocytes acquire immune priming functions through repetitive inflammatory stimuli, with recovery periods, causing transcriptome changes similar to those in the aged brain. Astrocytic priming by amyloid-β (Aβ) promoted cytokine release, leading to enhanced microglial phagocytic activity against Aβ. Conversely, APOE4 astrocytes showed impaired priming and reduced cytokine secretion in response to Aβ, leading to decreased microglial Aβ phagocytosis. Further, using a humanized APOE knock-in mouse model, we validated the positive effect of astrocyte priming on Aβ clearance in vivo. Our findings suggest that aging astrocytes may enhance Aβ clearance through the acquisition of immune priming functions and positively regulate Aβ clearance, while APOE4 impairs this process, leading to Aβ accumulation.
2025-07-06 | GSE274868 | GEO
Project description:Alzheimer's disease (AD)-associated allele, apolipoprotein E4 (APOE4), exhibits pathological characteristics in an age-dependent manner despite its presence from birth. The molecular and cellular changes leading to disease onset are largely unexplored. We observed using human-induced pluripotent stem cells (hiPSCs)-derived models that astrocytes acquire immune priming functions through repetitive inflammatory stimuli, with recovery periods, causing transcriptome changes similar to those in the aged brain. Astrocytic priming by amyloid-β (Aβ) promoted cytokine release, leading to enhanced microglial phagocytic activity against Aβ. Conversely, APOE4 astrocytes showed impaired priming and reduced cytokine secretion in response to Aβ, leading to decreased microglial Aβ phagocytosis. Further, using a humanized APOE knock-in mouse model, we validated the positive effect of astrocyte priming on Aβ clearance in vivo. Our findings suggest that aging astrocytes may enhance Aβ clearance through the acquisition of immune priming functions and positively regulate Aβ clearance, while APOE4 impairs this process, leading to Aβ accumulation.
2025-07-06 | GSE274869 | GEO
Project description:Unveiling age-associated immune priming properties of astrocytes for trigerring microglial Aβ clearance in an APOE isoform-dependent manner [ATAC-seq]
| PRJNA1148220 | ENA
Project description:Unveiling age-associated immune priming properties of astrocytes for trigerring microglial Aβ clearance in an APOE isoform-dependent manner [Ast_RNA-seq]
| PRJNA1148222 | ENA
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 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:One of the hallmarks of Alzheimer’s disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-β (Aβ) peptide. ApoE influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aβ in the brain. In addition to influencing Aβ metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1∆E9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Aβ morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.
2018-02-15 | GSE109906 | GEO
Project description:Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer’s disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of animal model of AD. Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and hypertrophic reactive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Ab aggregates in the brain of APP/PS1 mice An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients. Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.
2024-06-30 | GSE267554 | GEO
Project description:Alzheimer’s disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized AD patients with nonimmunized AD patients and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.
2025-03-03 | GSE282928 | GEO