Genomic regulation after CD40 stimulation in microglia: relevance to Alzheimer's disease.
Key pathological processes in Alzheimer's disease (AD) include the accumulation of amyloid beta peptide (Abeta) which, in excess, triggers pathological cascades including widespread inflammation, partly reflected by chronic microglial activation. It has previously been suggested that CD40/CD40L interaction promotes AD like pathology in transgenic mice. Thus, amyloid burden, gliosis and hyperphosphorylation of tau are all reduced in transgenic models of AD lacking functional CD40L. We therefore hypothesized that cellular events leading to altered APP metabolism, inflammation and increased tau phosphorylation underlying these observations would be regulated at the genomic level. In the present report, we used the Affymetrix (GeneChip) oligonucleotide microarray U133A to gain insight into the global and simultaneous transcriptomic changes in response to microglia activation after CD40/CD40L ligation. As expected, regulation of elements of the NF-kappaB signaling, chemokine and B cell signaling pathways was observed. Taken together, our data also suggest that CD40 ligation in human microglia specifically perturbs many genes associated with APP processing.
Ait-Ghezala
Ghania
G
The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. gaitghezala@rfdn.org
Mathura
Venkatarajan S
VS
Laporte
Vincent
V
Quadros
Amita
A
Paris
Daniel
D
Patel
Nikunj
N
Volmar
Claude-Henry
CH
Kolippakkam
Deepak
D
Crawford
Fiona
F
Mullan
Mike
M
D000544:Alzheimer Disease / Q000235:genetics* / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000494:pharmacology*; D023201:CD40 Ligand / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D017628:Microglia / Q000276:immunology / Q000502:physiology*; D008954:Models, Biological; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000276:immunology
D016229:Amyloid beta-Peptides; D019013:CD40 Antigens; D015850:Interleukin-6; D023201:CD40 Ligand