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Published online before print December 19, 2005

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(Journal of Leukocyte Biology. 2006;79:596-610.)
© 2006 by Society for Leukocyte Biology

Gene expression changes by amyloid ß peptide-stimulated human postmortem brain microglia identify activation of multiple inflammatory processes

Douglas G. Walker^*,1, John Link, Lih-Fen Lue^*, Jessica E. Dalsing-Hernandez^* and Barry E. Boyes

^* Laboratory of Neuroinflammation, Sun Health Research Institute, Sun City, Arizona; and
Agilent Technologies, Wilmington, Delaware

¹ Correspondence: Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351. E-mail: douglas.walker{at}sunhealth.org

A central feature of the inflammatory pathology in Alzheimer’s disease is activated microglia clustered around aggregated amyloid ß (Aß) peptide-containing plaques. In vitro-cultured microglia can be activated to an inflammatory state by aggregated Aß with the induction of a range of different neurotoxic factors and provide a model system for studying microglia Aß interactions. Gene expression responses of human postmortem brain-derived microglia to aggregated Aß were measured using whole genome microarrays to address the hypothesis that Aß interactions with human microglia primarily induce proinflammatory genes and not activation of genes involved in Aß phagocytosis and removal. The results demonstrated that Aß activation of microglia induced a large alteration in gene transcription including activation of many proinflammatory cytokines and chemokines, most notably, interleukin (IL)-1ß, 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 Aß 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 Aß induces multiple genes that could be involved in inflammatory responses contributing to neurodegenerative processes.

Key Words: calgranulin • cytokine • metalloproteinase

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