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Microglial APOE3 Christchurch protects neurons through suppression of ferroptosis in a human iPSC-derived Alzheimer’s disease model

ABSTRACT: Microglial APOE3 Christchurch protects neurons through suppression of ferroptosis in a human iPSC-derived Alzheimer’s disease model

PROVIDER: PRJNA1004304 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25604884.fastq.gz	Fastqsanger.gz
	SRR25604885.fastq.gz	Fastqsanger.gz
	SRR25604886.fastq.gz	Fastqsanger.gz
	SRR25604887.fastq.gz	Fastqsanger.gz

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Microglial APOE3 Christchurch protects neurons through suppression of ferroptosis in a human iPSC-derived Alzheimer’s disease model

Project description:Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder characterized by extracellular amyloid plaque and neuronal tangle formation. A 2019 study discovered an association between the APOE3 Christchurch (APOE3Ch) variant and delayed AD progression in a PSEN1 mutation carrier. However, whether the APOE3Ch variant is causal to the delayed onset of AD and what is the underlying mechanism remains to be explored. In this study, we established neuron-microglia cocultures and neuroimmune organoids using CRISPR/Cas9-edited isogenic APOE3 and APOE3Ch microglia derived from human induced pluripotent stem cells (hiPSCs) along with PSEN1 mutant neurons or brain organoids. We show that APOE3Ch microglia exhibit enhanced phagocytic capacity and increased Tau clearance in neuron-microglia co-cultures. Moreover, APOE3Ch microglia were able to reduce phosphorylated Tau levels in PSEN1 mutant brain organoids. We also demonstrated that APOE3Ch microglia could preserve neural network activity in co-cultured PSEN1 neurons when challenged with synaptosomes prepared from AD patient brains. RNA-seq analysis identified phagocytosis and ferroptosis among pathways of differentially expressed genes from APOE3 and APOE3Ch microglia. Subsequent validation analyses established a causal link between reduced ferroptosis and enhanced phagocytosis including Tau clearance by APOE3Ch microglia, providing mechanistic insights into the neuroprotective role of APOE3Ch microglia. These findings together demonstrate that the APOE3Ch variant plays a causal role in microglial neuroprotection which can be exploited in therapeutic development for AD.

2024-12-27 | GSE240609 | GEO

Distinct tau neuropathology and cellular profiles of a APOE3 Christchurch homozygote protected against Autosomal Dominant Alzheimer’s dementia

Project description:We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer’s disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer’s symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant impacts the distribution of tau pathology, modulates age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.

2022-08-26 | GSE206744 | GEO

Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer's disease

Project description:Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer's disease

| PRJNA801614 | ENA

Distinct tau neuropathology and cellular profiles of a APOE3 Christchurch homozygote protected against Autosomal Dominant Alzheimer’s dementia

Project description:Distinct tau neuropathology and cellular profiles of a APOE3 Christchurch homozygote protected against Autosomal Dominant Alzheimer’s dementia

| PRJNA851960 | ENA

Voluntary exercise alleviates neural functional deficits in Parkinson’s disease mice by inhibiting microglial ferroptosis via SLC7A11/ALOX12 axis

Project description:Microglia are more susceptible to ferroptosis compared to neurons and astrocytes, which may compromise their phagocytic and clearance capabilities of α-synuclein (α-syn) in Parkinson’s disease (PD). While the beneficial effects of physical exercise (PE) on reducing α-syn deposition in PD have been highlighted, the role of PE in modulating microglial ferroptosis remains unclear. This study focuses on the impact of exercise on inhibiting microglial ferroptosis and mitigating α-syn accumulation. We demonstrate that voluntary exercise effectively inhibits microglial ferroptosis. Mechanistically, PE-induced upregulation of SLC7A11 inhibits microglial ferroptosis by suppressing ALOX12, thereby enhancing microglial phagocytosis and clearance of α-syn, which is paralleled by improvements in neurological function in PD mice. Collectively, these findings not only underscore the critical role of microglial ferroptosis in the pathological progression of PD but also elucidate the molecular mechanism by which PE attenuates microglial ferroptosis via the SLC7A11/ALOX12 axis.

2025-09-29 | GSE309457 | GEO

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer’s Disease Model

Project description:Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer’s Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of Aβ and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis.

2024-10-25 | GSE248020 | GEO

AS-exos exacerbates microglial ferroptosis-driven neuroinflammation

Project description:AS-exos exacerbates microglial ferroptosis-driven neuroinflammation

| PRJNA1046021 | ENA

APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition

Project description:The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with attenuation of tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier. However, the specific molecular mechanisms enabling the E3S/S mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse ApoE with wild-type human E3 or E3S/S on a tauopathy background. The R136S mutation markedly decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in theta and gamma powers. Additionally, the R136S mutation reduced interferon response to tau pathology in both mouse and human microglia, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type E3 with a cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the R136S mutation across brain cell types. Thus, suppression of microglial cGAS-STING-IFN pathway plays a central role in mediating the protective effects of R136S against tauopathy.

2025-06-15 | GSE297721 | GEO

Human Apoe3 and Apoe4 alleles have differential effects on mouse olfactory epithelium

Project description:Alzheimer’s Disease (AD) is a progressive age-dependent disorder whose risk is determined in large part by genetic factors. We investigated the effects of human APOE3 and APOE4 alleles on the mouse olfactory epithelium.

2021-07-30 | GSE181038 | GEO

APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition [bulk RNA-seq]

2025-06-15 | GSE297743 | GEO