TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice

Institute of Clinical Neuroanatomy, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
Glia (Impact Factor: 6.03). 10/2008; 56(13):1438-47. DOI: 10.1002/glia.20710
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is characterized by extracellular deposits of amyloid-beta protein which attract dense clusters of microglial cells. Here, we analyzed amyloid plaque-associated areas in aged APP23 transgenic mice, an animal model of AD, by combining laser microdissection with microarray analysis and quantitative RT-PCR (qPCR). By comparing gene expression profiles, we found that 538 genes (1.3% of a total of 41,234 analyzed genes) were differentially expressed in plaque-associated versus plaque-free tissue of aged APP23 transgenic mice. One of these genes is the microglia-associated triggering receptor expressed on myeloid cells (TREM2) which enhances phagocytosis, but abrogates cytokine production as well as TLR and Fc receptor-mediated induction of TNF secretion. Western Blot analysis demonstrated an upregulation of TREM2 protein in APP23 transgenic compared with nontransgenic mice. Confocal imaging studies, furthermore, confirmed colocalization of TREM2 protein with microglia. Thus, when TREM2 is induced on microglia in plaque-loaded brain areas the respective signaling may prevent inflammation-induced bystander damage of neurons. At the same time, TREM2 signaling may also account for the failure to sufficiently eliminate extracellular amyloid with the help of a systemic immune response.

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    • "These findings have prompted studies of TREM2 in other neurodegenerative conditions such as Alzheimer's disease (AD). TREM2 has been reported to be up-regulated in mouse models of AD (Frank et al., 2008), anddcruciallyd2 independent studies have found that variants of TREM2 are associated with a greater risk of developing AD * Corresponding authors at: Institute of Neuropathology, University Hospital of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland. Tel.: þ41-44-255- 2108; fax: þ41-44-255-4402. "
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    ABSTRACT: Dysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly up-regulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2(-/-) mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation but does not noticeably modulate the pathogenesis of experimental prion infections. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of aging 02/2015; 36(5). DOI:10.1016/j.neurobiolaging.2015.02.019 · 4.85 Impact Factor
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    • "This increase remained statistically significant when normalizing TREM2 levels to the expression of a microglial marker Iba-1, suggesting that the upregulation of TREM2 was attributed to the enhanced expression in individual microglia rather than the increase in total microglia numbers. This observation was in line with previous findings from Frank et al (2008), who showed that TREM2 expression was increased in amyloid plaqueassociated microglia in aged APP23 transgenic mice. More recently, by using TgCRND8 mice, another transgenic mouse model of AD, Guerreiro et al (2013) found that the expression of TREM2 was remarkably increased in microglia , providing more support to our findings. "
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    ABSTRACT: Triggering receptor expressed on myeloid cells 2 gene (TREM2) is a recently identified susceptibility gene for Alzheimer's disease (AD), since its low-frequency variants increase the risk of this disease with an odds ratio similar to that of one APOE ɛ4 allele. To date, the expression and biological functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was up-regulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this up-regulation was attributed to the increased amyloid-β (Aβ) 1-42 levels in brain. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Aβ1-42 phagocytosis and inhibited Aβ1-42-triggered pro-inflammatory responses. Meanwhile, this modulation was depended on DAP12, the adapter protein of TREM2. More importantly, overexpression of TREM2 in brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Aβ deposition, neuroinflammation and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the up-regulation of TREM2 serves as a compensatory response to Aβ1-42 and subsequently protects against AD progression via modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.Neuropsychopharmacology accepted article preview online, 22 July 2014; doi:10.1038/npp.2014.164.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; 39(13). DOI:10.1038/npp.2014.164 · 7.83 Impact Factor
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    • "Recent studies link genetic variants of TREM2, a protein regulating the activation and phagocytic functions of myeloid cells, with the risk of developing AD (Guerreiro and others 2013; Jonsson and others 2013). TREM2 has a balancing role between phagocytic and pro-inflammatory microglial activities and is expressed in microglia around plaques (Frank and others 2008). Similarly, dysregulation of the complement system in humans has been associated with AD (Lambert and others 2009; McGeer and McGeer 2002). "
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