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-beta (Abeta) 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 Abeta peptide. Prompted by the fact that soluble Abeta(1-42) (sAbeta(1-42))-stimulated primary rat microglia produce more tumor necrosis factor-alpha (TNF-alpha) than fibrillar Abeta(1-42) (fAbeta(1-42))-stimulated microglia, we examined gene expression in these cells following stimulation using cDNA arrays. This analysis confirms the upregulation caused by both sAbeta(1-42) and fAbeta(1-42) of pro-inflammatory molecules such as TNF-alpha, interleukin-1beta and macrophage inflammatory protein-1alpha. In addition, other transcripts not previously described in the context of Abeta-induced microglial activation were identified. The modulation of some of these genes within microglial cells seems to be specific to sAbeta(1-42) as compared to fAbeta(1-42) suggesting that different forms of Abeta may activate distinct pathways during the progression of AD. Importantly, we demonstrate that Pde4B, a cAMP-specific phosphodiesterase, is upregulated by Abeta and results in an increased production of TNF-alpha. Inhibition of Pde4B reduces by up to 70% the release of TNF-alpha from sAbeta-stimulated microglial cells, implicating cAMP as an important mediator of Abeta-induced microglial activation.
Sebastiani
Giovanna
G
Neurochem Inc., 275, boul. Armand-Frappier, Laval, QC, Canada H7V 4A7.
Morissette
Céline
C
Lagacé
Caroline
C
Boulé
Marie
M
Ouellette
Marie-Josée
MJ
McLaughlin
Richard W
RW
Lacombe
Diane
D
Gervais
Francine
F
Tremblay
Patrick
P
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002469:Cell Separation; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D009693:Nucleic Acid Hybridization; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020889:Rolipram / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016207:Cytokines; D018076:DNA, Complementary; D007527:Isoenzymes; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram