Gene expression changes by amyloid beta peptide-stimulated human postmortem brain microglia identify activation of multiple inflammatory processes.
A central feature of the inflammatory pathology in Alzheimer's disease is activated microglia clustered around aggregated amyloid beta (Abeta) peptide-containing plaques. In vitro-cultured microglia can be activated to an inflammatory state by aggregated Abeta with the induction of a range of different neurotoxic factors and provide a model system for studying microglia Abeta interactions. Gene expression responses of human postmortem brain-derived microglia to aggregated Abeta were measured using whole genome microarrays to address the hypothesis that Abeta interactions with human microglia primarily induce proinflammatory genes and not activation of genes involved in Abeta phagocytosis and removal. The results demonstrated that Abeta activation of microglia induced a large alteration in gene transcription including activation of many proinflammatory cytokines and chemokines, most notably, interleukin (IL)-1beta, IL-8, and matrix metalloproteinases (MMP), including MMP1, MMP3, MMP9, MMP10, and MMP12. All of these genes could amplify ongoing inflammation, resulting in further neuronal loss. Changes in expression of receptors associated with Abeta phagocytosis did not match the changes in proinflammatory gene expression. Time-course gene expression profiling, along with real-time polymerase chain reaction validation of expression changes, demonstrated an acute phase of gene induction for many proinflammatory genes but also chronic activation for many other potentially toxic products. These chronically activated genes included indoleamine 2,3-dioxygenase and kynureninase, which are involved in formation of the neurotoxin quinolinic acid, and S100A8, a potential proinflammatory chemokine. These studies show that activation of microglia by Abeta induces multiple genes that could be involved in inflammatory responses contributing to neurodegenerative processes.
Walker
Douglas G
DG
Laboratory of Neuroinflammation, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. douglas.walker@sunhealth.org
Link
John
J
Lue
Lih-Fen
LF
Dalsing-Hernandez
Jessica E
JE
Boyes
Barry E
BE
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D040501:Calgranulin A / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000032:analysis / Q000235:genetics; D004660:Encephalitis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D005911:Gliosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D017378:Quinolinic Acid / Q000378:metabolism; D012016:Reference Values; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D016229:Amyloid beta-Peptides; D040501:Calgranulin A; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004247:DNA; D017378:Quinolinic Acid