title: Genomic regulation after CD40 stimulation in microglia: relevance to Alzheimer's disease.
abstract: 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.
authors.affiliation: The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. gaitghezala@rfdn.org
authors.forename: Ghania
authors.initials: G
authors.lastname: Ait-Ghezala
authors.forename: Venkatarajan S
authors.initials: VS
authors.lastname: Mathura
authors.forename: Vincent
authors.initials: V
authors.lastname: Laporte
authors.forename: Amita
authors.initials: A
authors.lastname: Quadros
authors.forename: Daniel
authors.initials: D
authors.lastname: Paris
authors.forename: Nikunj
authors.initials: N
authors.lastname: Patel
authors.forename: Claude-Henry
authors.initials: CH
authors.lastname: Volmar
authors.forename: Deepak
authors.initials: D
authors.lastname: Kolippakkam
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
authors.forename: Mike
authors.initials: M
authors.lastname: Mullan
mesh_terms: 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
chemical_list: D016229:Amyloid beta-Peptides; D019013:CD40 Antigens; D015850:Interleukin-6; D023201:CD40 Ligand