The cAMP-specific phosphodiesterase 4B mediates Aβ-induced microglial activation

Microglial activation is a key player in the degenerative process that accompanies the deposition of amyloid-beta (AP) 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 AP peptide. Prompted by the fact that soluble AP(1-42) (sA beta(1-42))-stimulated primary rat microglia produce more tumor necrosi's factor-alpha (TNF-alpha) than fibrillar A beta(1-42) (fA beta(1-42))-stimulated microglia, we examined gene expression in these cells following stimulation using cDNA arrays. This analysis confirms the upregulation caused by both sA beta(1-42) and fA beta(1-42) of pro-inflammatory Molecules Such as TNF-alpha, interleukin-I beta and macrophage inflammatory protein-1 alpha. In addition, other transcripts not previously described in the context of A beta-induced microglial activation were identified. The modulation of some of these genes within microglial cells seems to be specific to sA beta(1-42) as compared to fA beta(1-42) suggesting that different forms of AP may activate distinct pathways during the progression of AD. Importantly, we demonstrate that Pde4B, a cAMP-specific phosphodiesterase, is upregulated by AP and results in an increased production of TNF-alpha. Inhibition of Pde4B reduces by up to 70% the release of TNF-alpha from sA beta-stimulated microglial cells, implicating cAMP as an important mediator of Ap-induced microglial activation. (c) 2005 Elsevier Inc. All rights reserved.