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.
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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;
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ABSTRACT: The 5XFAD early onset mouse model of Alzheimer's disease (AD) is gaining momentum. Behavioral, electrophysiological and anatomical studies have identified age-dependent alterations that can be reminiscent of human AD. However, transcriptional changes during disease progression have not yet been investigated. To this end, we carried out a transcriptomic analysis on RNAs from the neocortex and the hippocampus of 5XFAD female mice at the ages of one, four, six and nine months (M1, M4, M6, M9).Molecular Neurodegeneration 09/2014; 9(1):33. · 5.29 Impact Factor
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ABSTRACT: During the development of Alzheimer’s disease (AD), changes in gene expression occur at many stages of disease progression. Early changes may be causal, possibly contributing to initial pathology, whereas later changes may be consequential, due to synaptic and neuronal damage. Eventually, amyloid and/or tau deposition and gliosis are thought to result in altered expression of genes including those of the immune system. Although these latter changes have often been thought of as secondary, and therefore of little note, recent analyses have suggested that genetic variability in immune processes, particularly with respect to microglial responses, is important in determining the risk of individuals presenting with the disease. Although mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1) or PSEN2 that lead to raised levels of a range of amyloidβ (Aβ) peptides are sufficient to result in Alzheimer’s disease in humans, phosphorylation of microtubule-associated protein tau (tau) and the development of tangles is an essential step in the course of the disease. The relative contribution of these two elements to different aspects of the disease is still a matter of controversy.Cell Reports 01/2015; 5(4). · 7.21 Impact Factor