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

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide, but no effective treatments are available, in large part because the mechanisms underlying this disease are unclear. 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 propose 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, and the role of AD genetic risk variants in this process. Likewise, in vitro LPS-activation of brain immune cells models has been used to trigger the inflammasome as a similar approach. Nevertheless, the resemblance of these models to the AD brain has never been comprehensively studied on a genome-wide scale. We used RNA-seq to quantify the global transcriptional response of cultured innate immune cells treated with synthetic Aβ or LPS/INFγ and to analyze the resemblance of these responses to the AD brain transcriptome. We observed a robust transcriptional response to LPS/INFγ, but surprisingly we found little to no response to Aβ. The findings were consistent across all cellular models, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes), and when different formulations and concentrations of Aβ were employed. Our results reveal that synthetic Aβ does not produce a robust transcriptional response in these cells, suggesting that alternative in vitro models to mimic the inflammatory estate in the AD brain, such as the use of LPS-activated iPSCs-derived brain immune cells might be the best in vitro model to further understand the molecular mechanisms underlying this disease.