Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems

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 orig...

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Published in:	Journal of neuroinflammation Vol. 19; no. 1; pp. 99 - 12
Main Authors:	Quiroga, I Y, Cruikshank, A E, Bond, M L, Reed, K S M, Evangelista, B A, Tseng, J H, Ragusa, J V, Meeker, R B, Won, H, Cohen, S, Cohen, T J, Phanstiel, D H
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 23-04-2022 BioMed Central BMC
Subjects:	Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer's disease Amyloid beta-Peptides - metabolism Amyloid beta-protein Astrocytes Brain Cell activation Cell culture Cell Culture Techniques Cell lines Cognitive ability Development and progression Diagnosis Genetic transcription Genomes Health aspects Humans Hypotheses Immune system Immunity, Innate Induced Pluripotent Stem Cells - metabolism Inflammation Lipopolysaccharide Lipopolysaccharides Lipopolysaccharides - pharmacology Macrophages Microglia Microglia - metabolism Neurodegenerative diseases Neurodegenerative Diseases - metabolism Pluripotency RNA-seq Stem cells Transcription Transcriptomics United States United States > US Lipopolysaccharide Alzheimer’s disease RNA-seq Microglia
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Summary:	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. 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. We 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. We 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. These 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1742-2094 1742-2094
DOI:	10.1186/s12974-022-02459-1