Amyloid beta acts synergistically as a pro-inflammatory cytokine

The amyloid beta (A{beta}) peptide is believed to play a central role in Alzheimers disease (AD), the most common age-related neurodegenerative disorder. However, the natural, evolutionarily-selected functions of A{beta} are incompletely understood. Here, we report that nanomolar concentrations of A{beta} act synergistically with known cytokines to promote pro-inflammatory activation in primary human astrocytes (a cell type increasingly implicated in brain aging and AD). Using transcriptomics (RNA-seq), we show that A{beta} can directly substitute for the complement component C1q in a cytokine cocktail previously shown to induce astrocyte immune activation. Furthermore, we show that astrocytes synergistically activated by A{beta} have a transcriptional signature similar to neurotoxic "A1" astrocytes known to accumulate with age and in AD. Interestingly, we find that this biological action of A{beta} at low concentrations is distinct from the transcriptome changes induced by the high/supraphysiological doses of A{beta} often used in in vitro studies. Collectively, our results suggest an important, cytokine-like function for A{beta} and a novel mechanism by which it may directly contribute to the neuroinflammation associated with brain aging and AD.