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

Abstract

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.

Intracerebral Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells Reduces Amyloid-Beta Deposition and Rescues Memory Deficits in Alzheimer's Disease Mice by Modulation of Immune Responses

“…The aggregated Ab protein, which is present in senile plaques of AD patients, activates microglia to produce neurotoxic substances that contribute to the neurodegenerative changes [41][42][43][44]. In accordance with previous reports in AD and AD animal models, we wondered whether activated microglia by BM-MSCs produce proinflammatory cytokines.…”

Evaluating the role of Toll-like receptors in diseases of the central nervous system

“…Activation of microglia results in the production of NO, oxygen free radicals, proteases, adhesion molecules and proinflammatory cytokines such as TNFα, IL-1β, LT-α, and IL-6 [27][28][29][30][31]. It is thought that the overproduction of these inflammatory mediators is important in the degenerative process in patients with AD [32].…”

Melatonin treatment in old mice enables a more youthful response to LPS in the brain

“…In humans, high synovial fluid levels S100A8/A9 are measured in rheumatoid arthritis; concentration increases with disease severity and resistance to treatment (Frosch et al, 2000). S100A8 mRNA expression is greatly induced by β-amyloid in microglia cultured from post-mortem human brain tissue (Walker et al, 2006), while S100A9 protein is found in reactive microglia in Alzheimer's disease brains (Akiyama et al, 1994). Excessive levels of calprotectin can induce symptoms of zinc deficiency and reduced resistance to infection (Sampson et al, 2002), common conditions in the elderly.…”