Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems
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ABSTRACT:
PROVIDER: PRJNA750801 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR15301012_1.fastq.gz | Fastqsanger.gz | |||
| SRR15301012_2.fastq.gz | Fastqsanger.gz | |||
| SRR15301013_1.fastq.gz | Fastqsanger.gz | |||
| SRR15301013_2.fastq.gz | Fastqsanger.gz | |||
| SRR15301016_1.fastq.gz | Fastqsanger.gz |
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Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of Amyloid beta (Aβ) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. The combination of these observations has led to the proposal of Aβ as the main trigger to induce the proinflammatory activation of immune brain cells that culminates in neuronal damage and cognitive decline. In order to test this hypothesis, many in vitro systems have been established to study Aβ-mediated activation of innate immune cells. Nevertheless, the resemblance of these models to the AD brain has never been comprehensively studied on a genome-wide scale. To address this, we used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model AD and its similarities to primary brain immune cells. We then analysed the transcriptional response of different innate immune cells to synthetic Aβ. We found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) is the in vitro cell model that best resembles primary microglia, but surprisingly, synthetic Aβ does not trigger a robust transcriptional response in any of the cellular models analysed, even when different formulations and concentrations of Aβ were employed. Finally we found that the alternative use of bacterial LPS and INF to activate the inflammasome in microglia, induces the transcription of genes that are also elevated in disease associated microglia present in the AD brain suggesting the suitability of this model to study AD-related neuroinflammation.
2021-07-30 | GSE181153 | GEO
Project description:BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of amyloid beta (Aβ) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. These observations have given rise to the theory that Aβ is the primary trigger of AD, and induces proinflammatory activation of immune brain cells (i.e., microglia), which culminates in neuronal damage and cognitive decline. To test this hypothesis, many in vitro systems have been established to study Aβ-mediated activation of innate immune cells. Nevertheless, the transcriptional resemblance of these models to the microglia in the AD brain has never been comprehensively studied on a genome-wide scale.MethodsWe used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model neuroinflammation in AD, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes) and their similarities to primary cells in the AD brain. We then analyzed the transcriptional response of these innate immune cells to synthetic Aβ or LPS and INFγ.ResultsWe found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) are the in vitro cell model that best resembles primary microglia. Surprisingly, synthetic Aβ does not trigger a robust transcriptional response in any of the cellular models analyzed, despite testing a wide variety of Aβ formulations, concentrations, and treatment conditions. Finally, we found that bacterial LPS and INFγ activate microglia and induce transcriptional changes that resemble many, but not all, aspects of the transcriptomic profiles of disease associated microglia (DAM) present in the AD brain.ConclusionsThese results suggest that synthetic Aβ treatment of innate immune cell cultures does not recapitulate transcriptional profiles observed in microglia from AD brains. In contrast, treating IMGL with LPS and INFγ induces transcriptional changes similar to those observed in microglia detected in AD brains.
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