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 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 INF𝛄 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. This study features seven different cell types that were treated with various combinations of PBS (control for each treatment), Aβ (in various forms and concentrations), and a combination of LPS and IFN-gamma, with or without 10% FBS, prior to RNA extraction. There are 74 samples in total (37 unique conditions, 2 biological replicates each). Experiments were conducted across 10 days (experiment number).