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. 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. In order 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. To address this, 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. 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 similar to those observed in disease associated microglia present in the AD brain, suggesting the potential suitability of this model to study AD-related neuroinflammation.

A Coarse-Grained Molecular Dynamics Investigation on Spontaneous Binding of Aβ1-40Fibrils with Cholesterol-mixed DPPC Bilayers

“…Amyloid fibrils are misfolded, β-sheet-rich, aggregated proteins that play a key role in more than 20 diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), type 2 diabetes, HIV, and different forms of systemic amyloidosis [1][2][3][4][5][6][7]. Conditions involving amyloid fibrils formation, which are commonly known as protein misfolding diseases, affect millions of people around the world [8,9]. According to the amyloid cascade hypothesis, in the brain of AD patients the amyloid β peptide (Aβ) undergoes conformational changes to form water-insoluble Aβ fibrils [10,11].…”