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
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.
Available from: jneuroinflammation.com
- "Interestingly, TREM2 variants have recently been associated with late-onset Alzheimer's disease (AD) and frontotemporal lobe dementia (FTD)8910. Notably, TREM2 was found to be upregulated in microglia or myeloid cells surrounding characteristic amyloid plaques in mouse models of AD111213. The role of TREM2 in the pathogenesis of AD remains to be determined, and studies with transgenic mouse models showed controversial effects. "
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ABSTRACT: Background: Triggering receptor expressed on myeloid cells-2 (TREM2) exerts important functions in the regulation of monocytes, like dendritic cells, osteoclasts, tissue macrophages, and microglia. Mutations in TREM2 are associated with several diseases, including Nasu-Hakola disease, frontotemporal dementia, and Alzheimer's disease (AD). TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis. Findings: We show that inhibition of γ-secretase-dependent cleavage of the TREM2 C-terminal fragment in cellular membranes interferes with TREM2-dependent signaling and cellular function. Inhibition of γ-secretase decreases membrane-proximal signaling and intracellular Ca2+ response. Decreased signaling alters morphological changes and phagocytic activity of cells upon selective stimulation of TREM2. Conclusions: The data demonstrate the importance of γ-secretase-dependent intramembrane processing in TREM2-mediated signaling and, thus, a functional relation of two AD-associated proteins.
Available from: Caihong Zhu
- "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.
Available from: Noel Derecki
- "TREM2 seems to be crucial for brain homeostasis, since its activation stimulates the phagocytic activity in microglia without causing inflammation . In APP transgenic mice, TREM2 is up-regulated in microglial cells in the vicinity of amyloid plaques . However, Nasu–Hakola disease patients do not overly develop Aβ plaques and therefore the relevance of TREM2 in sporadic AD needs to be investigated further. "
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ABSTRACT: Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer's disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies. In a mouse model of Rett syndrome, bone marrow transplant and CNS engraftment of microglia-like cells were associated with surprising improvements in pathology-these benefits were abrogated by block of phagocytic function. In Alzheimer's disease, large-scale genome-wide association studies have been brought to bear as a method of identifying previously unknown susceptibility genes, which highlight microglial receptors as promising novel targets for therapeutic modulation. Multi-photon in vivo microscopy has provided a method of directly visualizing the effects of manipulation of these target genes. Here, we review the latest findings and concepts emerging from the rapidly growing body of literature exemplified for Rett syndrome and late-onset, sporadic Alzheimer's disease.
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