The cAMP-specific phosphodiesterase 4B mediates Abeta-induced microglial activation.

Microglial activation is a key player in the degenerative process that accompanies the deposition of amyloid-β (Aβ) peptide into senile plaques in Alzheimer's disease (AD) patients. The goal of this study is to identify novel genes involved in microglial activation in response to Aβ peptide. Prompted by the fact that soluble Aβ1–42 (sAβ1–42)-stimulated primary rat microglia produce more tumor necrosis factor-α (TNF-α) than fibrillar Aβ1–42 (fAβ1–42)-stimulated microglia, we examined gene expression in these cells following stimulation using cDNA arrays. This analysis confirms the upregulation caused by both sAβ1–42 and fAβ1–42 of pro-inflammatory molecules such as TNF-α, interleukin-1β and macrophage inflammatory protein-1α. In addition, other transcripts not previously described in the context of Aβ-induced microglial activation were identified. The modulation of some of these genes within microglial cells seems to be specific to sAβ1–42 as compared to fAβ1–42 suggesting that different forms of Aβ may activate distinct pathways during the progression of AD. Importantly, we demonstrate that Pde4B, a cAMP-specific phosphodiesterase, is upregulated by Aβ and results in an increased production of TNF-α. Inhibition of Pde4B reduces by up to 70% the release of TNF-α from sAβ-stimulated microglial cells, implicating cAMP as an important mediator of Aβ-induced microglial activation.