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.
"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. "
"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. "
[Show abstract][Hide abstract] 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.
"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. "
[Show abstract][Hide abstract] 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 · 7.05 Impact Factor
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