Abstract
BackgroundMicroglia are associated with neuritic plaques in Alzheimer disease (AD) and serve as a primary component of the innate immune response in the brain. Neuritic plaques are fibrous deposits composed of the amyloid beta-peptide fragments (Abeta) of the amyloid precursor protein (APP). Numerous studies have shown that the immune cells in the vicinity of amyloid deposits in AD express mRNA and proteins for pro-inflammatory cytokines, leading to the hypothesis that microglia demonstrate classical (Th-1) immune activation in AD. Nonetheless, the complex role of microglial activation has yet to be fully explored since recent studies show that peripheral macrophages enter an "alternative" activation state.MethodsTo study alternative activation of microglia, we used quantitative RT-PCR to identify genes associated with alternative activation in microglia, including arginase I (AGI), mannose receptor (MRC1), found in inflammatory zone 1 (FIZZ1), and chitinase 3-like 3 (YM1).ResultsOur findings confirmed that treatment of microglia with anti-inflammatory cytokines such as IL-4 and IL-13 induces a gene profile typical of alternative activation similar to that previously observed in peripheral macrophages. We then used this gene expression profile to examine two mouse models of AD, the APPsw (Tg-2576) and Tg-SwDI, models for amyloid deposition and for cerebral amyloid angiopathy (CAA) respectively. AGI, MRC1 and YM1 mRNA levels were significantly increased in the Tg-2576 mouse brains compared to age-matched controls while TNFα and NOS2 mRNA levels, genes commonly associated with classical activation, increased or did not change, respectively. Only TNFα mRNA increased in the Tg-SwDI mouse brain. Alternative activation genes were also identified in brain samples from individuals with AD and were compared to age-matched control individuals. In AD brain, mRNAs for TNFα, AGI, MRC1 and the chitinase-3 like 1 and 2 genes (CHI3L1; CHI3L2) were significantly increased while NOS2 and IL-1β mRNAs were unchanged.ConclusionImmune cells within the brain display gene profiles that suggest heterogeneous, functional phenotypes that range from a pro-inflammatory, classical activation state to an alternative activation state involved in repair and extracellular matrix remodeling. Our data suggest that innate immune cells in AD may exhibit a hybrid activation state that includes characteristics of classical and alternative activation.
Highlights
Microglia are associated with neuritic plaques in Alzheimer disease (AD) and serve as a primary component of the innate immune response in the brain
Alternative activation gene expression profiles have been described for tissue macrophages found in the periphery but have not been identified for brain macrophages, the microglia
For genes commonly associated with classical activation, we found that NOS2 mRNA was expressed at wild-type levels while TNFα mRNA expression was slightly, but significantly elevated (Fig. 2A)
Summary
Microglia are associated with neuritic plaques in Alzheimer disease (AD) and serve as a primary component of the innate immune response in the brain. Numerous studies have shown that the immune cells in the vicinity of amyloid deposits in AD express mRNA and proteins for pro-inflammatory cytokines, leading to the hypothesis that microglia demonstrate classical (Th-1) immune activation in AD. The programmed response to acute stimuli includes the induction of a specific gene profile and the subsequent production of multiple cytoactive factors such as TNFα, NO and IL-1 that protect against tissue invaders. In peripheral macrophages, this first phase of an innate immune response has been described as classical immune activation [1,2,3]. IL-4 and IL-13 -mediated gene induction has been termed alternative activation and includes genes that produce arginase I (AG1), mannose receptors (MRC1) and genes associated with tissue remodeling such as Found in Inflammatory Zone 1 (FIZZ1) and chitinase 3-like 3 (YM1) [8,9,10,11]
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