TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice
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.
Article: Genetics of Alzheimer’s Disease[Show abstract] [Hide abstract]
ABSTRACT: The analyses of genetic factors contributing to Alzheimer's disease (AD) and other dementias have evolved at the same pace as genetic and genomic technologies are developed and improved. The identification of the first genes involved in AD arose from family-based studies, but risk factors have mainly been identified by studies comparing groups of patients with groups of controls. The best outcomes have been heavily associated with the capacity of interrogating genetic variability at the genome level without any particular a priori hypothesis. In this review we assess the role of genetic family studies in Alzheimer's disease and other dementias within the current status of dementias' and, particularly, AD's genetic architecture.Neurotherapeutics 10/2014; 11(4):732-737. DOI:10.1007/s13311-014-0295-9 · 3.88 Impact Factor
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ABSTRACT: Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer's disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2's involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45(hi)Ly6C(+) myeloid cells, but not on P2RY12(+) parenchymal microglia. In AD mice deficient for TREM2, the CD45(hi)Ly6C(+) macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2(+) macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics. © 2015 Jay et al.Journal of Experimental Medicine 03/2015; 212(3). DOI:10.1084/jem.20142322 · 13.91 Impact Factor
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ABSTRACT: Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.Acta Neuropathologica 01/2015; 129(3). DOI:10.1007/s00401-015-1388-1 · 9.78 Impact Factor