IRF-8 is Involved in Amyloid-β1-40 (Aβ1-40)-induced Microglial Activation: a New Implication in Alzheimer's Disease

It is well known that extracellular deposition of amyloid-beta (A beta) peptide and microglia-mediated neuroinflammation are major hallmarks of Alzheimer's disease (AD). Interferon regulatory factor-8 (IRF-8), an important transcription factor of the IRF family, is highly restricted in microglia in brains. The expression pattern and function of IRF-8 in AD need to be elucidated in order to provide novel therapies for the treatment of AD. In this study, our results indicated that expression of IRF-8 is significantly elevated in the brains and microglia of AD transgenic model Tg2576 mice. Notably, in vitro cell culture and reporter luciferase assay show that A beta(1-40) treatment promotes expression of IRF-8 at the transcriptional level. Silencing of IRF-8 in microglia abolished A beta(1-40)-induced elevation in typical activated microglia-related genes, including the microglial innate response receptor toll-like receptor 2 (TLR2), the chemotaxis gene purinergic receptor P2Y12R, and the proinflammatory cytokine IL-1 beta. However, overexpression of IRF-8 exacerbated the elevated expression of these proteins. Finally, the JAK2/STAT-1 pathway was found to mediate A beta(1-40)-induced elevation of IRF-8. Overall, this is the first time to report that IRF-8 is involved in microglial activation and neuroinflammation in AD.