Microglia-astrocyte interplay mitigates Aβ toxicity in a novel human 3D neurosphere model of Alzheimer’s Disease
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ABSTRACT:
PROVIDER: PRJNA1135476 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29819222_1.fastq.gz | Fastqsanger.gz | |||
| SRR29819222_2.fastq.gz | Fastqsanger.gz | |||
| SRR29819223_1.fastq.gz | Fastqsanger.gz | |||
| SRR29819223_2.fastq.gz | Fastqsanger.gz | |||
| SRR29819224_1.fastq.gz | Fastqsanger.gz |
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Project description:Microgliosis and astrogliosis characteristically occur at Aβ plaques in the brains of Alzheimer’s disease (AD) patients although the impact of gliosis in AD is poorly understood. We studied the impact of Aβ-induced gliosis using human induced pluripotent stem cell (hiPSC)-derived 3D neurospheres (hiNS), containing only astrocytes and neurons versus hiNS with the addition of iPSC-derived microglia (hiMG). Applying Aβ to hiNS containing only astrocytes and neurons triggered pathological features of AD including plaque-like aggregates, reactive astrocytes, oxidative stress, neuronal dysfunction and cell death. In contrast, when hiMG were combined with hiNS, infiltrating hiMG effectively phagocytose Aβ and facilitate neuroprotection. Our findings further support a pivotal role for microglia in modulating astrocyte Aβ responses by inducing AD-associated gene expression in astrocytes, including the upregulation of APOE, crucial for Aβ clearance. This model, highlighting the neuroprotective potential of microglia-astrocyte interactions, offers a novel platform for exploring AD mechanisms and novel therapeutic strategies.
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Project description:The innate immune system can develop a form of memory called priming, where prior exposure to a stimulus enhances subsequent responses. While well-characterized in peripheral immunity, its function in brain-resident cells such as astrocytes under non-disease conditions remains unclear. Here we show that human astrocytes derived from the induced pluripotent stem cells of healthy female donors, but not microglia, acquire a primed state following transient immune stimulations. Upon subsequent exposure to amyloid-β (Aβ), these astrocytes secrete elevated levels of cytokines and promote microglial Aβ uptake. In contrast, astrocytes carrying the Alzheimer’s disease (AD) risk allele APOE4 exhibit reduced priming and fail to support microglial phagocytosis. These findings are validated in astrocyte-microglial co-cultures, cerebral organoids, and male mice, where astrocyte priming enhances Aβ clearance in an APOE4-sensitive manner. Our findings identify astrocytic immune memory as a modulator of microglial function and Aβ pathology, providing insights into how early protective responses in AD may be disrupted by genetic risk factors.
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Project description:The innate immune system can develop a form of memory called priming, where prior exposure to a stimulus enhances subsequent responses. While well-characterized in peripheral immunity, its function in brain-resident cells such as astrocytes under non-disease conditions remains unclear. Here we show that human astrocytes derived from the induced pluripotent stem cells of healthy female donors, but not microglia, acquire a primed state following transient immune stimulations. Upon subsequent exposure to amyloid-β (Aβ), these astrocytes secrete elevated levels of cytokines and promote microglial Aβ uptake. In contrast, astrocytes carrying the Alzheimer’s disease (AD) risk allele APOE4 exhibit reduced priming and fail to support microglial phagocytosis. These findings are validated in astrocyte-microglial co-cultures, cerebral organoids, and male mice, where astrocyte priming enhances Aβ clearance in an APOE4-sensitive manner. Our findings identify astrocytic immune memory as a modulator of microglial function and Aβ pathology, providing insights into how early protective responses in AD may be disrupted by genetic risk factors.
2025-07-06 | GSE274869 | GEO
Project description:The innate immune system can develop a form of memory called priming, where prior exposure to a stimulus enhances subsequent responses. While well-characterized in peripheral immunity, its function in brain-resident cells such as astrocytes under non-disease conditions remains unclear. Here we show that human astrocytes derived from the induced pluripotent stem cells of healthy female donors, but not microglia, acquire a primed state following transient immune stimulations. Upon subsequent exposure to amyloid-β (Aβ), these astrocytes secrete elevated levels of cytokines and promote microglial Aβ uptake. In contrast, astrocytes carrying the Alzheimer’s disease (AD) risk allele APOE4 exhibit reduced priming and fail to support microglial phagocytosis. These findings are validated in astrocyte-microglial co-cultures, cerebral organoids, and male mice, where astrocyte priming enhances Aβ clearance in an APOE4-sensitive manner. Our findings identify astrocytic immune memory as a modulator of microglial function and Aβ pathology, providing insights into how early protective responses in AD may be disrupted by genetic risk factors.
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Project description:Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4
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Project description:Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4
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Project description:Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4
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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.
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