Modification: Trem2: Knock-Out
Disease Relevance: Nasu-Hakola Disease, Frontotemporal Dementia, Alzheimer's Disease
Strain Name: C57BL/6 -TREM2tm1cln
Genetic Background: C57BL/6
Availability: Available through Marco Colonna
Loss-of-function mutations in TREM2 cause Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) (Paloneva et al., 2002), a rare, autosomal-recessive disorder characterized by bone fractures and early onset frontotemporal dementia (Paloneva et al., 2002). TREM2 variants have also been associated with frontotemporal dementia in the absence of bone abnormalities (Guerreiro et al., 2013; Guerreiro et al., 2013; LaBer et al., 2014). Some variants may confer increased risk for Alzheimer’s disease and other neurodegenerative disorders (Jay et al., 2017; Yeh et al., 2017).
Trem2-/- mice may be used to study the biological consequences of the loss of TREM2 function. Trem2-/- mice have been crossed with APP and tau transgenic mice to study the effects of loss of TREM2 function in the context of amyloidosis and tauopathy.
Trem2-/- mice were created by targeted deletion of exons 3 and 4 (Turnbull et al., 2006). Trem2-/- mice are osteopenic (Otero et al., 2012), but they do not exhibit an obvious neurological phenotype (Poliani et al., 2015). However, Trem2-/- microglia have an altered transcriptome and an impaired response to a variety of brain injuries.
Compared with microglia isolated from wild-type mice, cells from Trem2-/- mice show dysregulation of genes associated with chemotaxis, cell motility, and response to wounds. There is also a slight, but statistically significant, increase in the expression of several genes that have been classified as homeostatic (i.e., expressed under basal conditions, but downregulated under pathological conditions), including Cx3cr1, Tmem119, Tgfbr1, P2ry12, Il10ra (Mazaheri et al., 2017).
Consistent with the gene-profiling results, microglial migration toward damaged sites was impaired in Trem2-/- mice. In an ex vivo migration assay, in which organotypic slices from test animals were co-cultured with slices from aged (plaque-depositing) APPPS1 mice, Trem2-/- microglia migrated significantly shorter distances into the APPPS1 slices than did wild-type microglia (Mazaheri et al., 2017). In vivo, wild-type microglia enthusiastically clustered around apoptotic neurons injected into the brain (Mazaheri et al., 2017) and adopted a “microglial neurodegenerative phenotype,” downregulating homeostatic genes and upregulating genes associated with inflammation (Krasemann et al., 2017), responses that were attenuated in Trem2-/- mice. Trem2-/- microglia were also slower to extend processes toward laser lesions made in the cortex than were microglia that express Trem2 (Mazaheri et al., 2017).
Trem2-/- mice do not exhibit spontaneous white-matter damage, a hallmark of Nasu-Hakola disease. However, white-matter microglia differ between wild-type and Trem2-/- mice: In the corpus callosum of wild-type mice, microglial number increases with age while microglial size remains stable, but the converse occurs in Trem2-/- mice—the number of white-matter microglia remains constant while there is an age-dependent decrease in microglial size (Poliani et al., 2015).
Trem2-/- mice also differ from wild-type mice in their responses to experimental demyelination induced by oral administration of the copper chelator cuprizone (CPZ). Compared with wild-type mice, Trem2-/- mice exhibit impaired clearance of myelin debris (Cantoni et al., 2015; Poliani et al., 2015), more severe and persistent loss of oligodendrocytes (Poliani et al., 2015), and more severe axon damage (Cantoni et al., 2015; Poliani et al., 2015). Microgliosis during the demyelinating phase is attenuated in Trem2-/- mice (Cantoni et al., 2015; Poliani et al., 2015), while the resolution of microgliosis during the remyelinating phase may be slowed (Poliani et al., 2015). Astrocytosis plateaus during the demyelinating phase in Trem2-/- mice, but continues to increase through the remyelinating phase in wild-type mice (Cantoni et al., 2015). Behaviorally, Trem2-/- mice given CPZ for 12 weeks perform worse on tests of motor coordination (pole test, inclined-screen test, rotarod) than do wild-type mice treated for the same period, although the genotypes do not differ in tests of locomotor activity, balance, or grip strength (Cantoni et al., 2015).
Trem2-/- mice also exhibit impaired microglial activation in experimental models of stroke. In a transient middle cerebral artery occlusion (MCAO) model, TREM2 deficiency did not affect the size of the lesion seven or 28 days post-stroke (Sieber et al., 2013). In a permanent MCAO model, functional deficits were more severe in Trem2-/- mice than wild-type mice (Kawabori et al., 2015).
Trem2-/- mice lose fewer neurons in the facial motor nucleus after facial nerve axotomy, compared with wild-type mice (Krasemann et al., 2017).
The Trem2 gene in 129P2/OlaHsd mouse embryonic stem cells (ESC) was modified through homologous recombination using a targeting vector designed to replace exons 3 and 4 with a floxed neomycin selection cassette. Mice were generated by injection of the genetically modified ESCs into C57BL/6 blastocysts. Chimeric animals were bred to Cre-expressing mice to delete the neomycin resistance gene. Progeny were back-crossed to C57BL/6 more than five times (Turnbull et al., 2006).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Cognitive Impairment
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
No spontaneous gliosis, but impaired microglial response to injury.
Changes in LTP/LTD
Last Updated: 18 Jan 2018
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