Modification: TREM2: Knock-Out
Disease Relevance: Nasu-Hakola Disease, Frontotemporal Dementia, Alzheimer's Disease
Strain Name: Trem2tm1(KOMP)Vlcg
Genetic Background: C57BL/6N
Availability: UC Davis KOMP Repository, Project VG10093, cryo-recovery or sperm
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.
The Trem2−/− (KOMP) mouse was created by the NIH Knockout Mouse Project. In this Trem2 knockout line, the entire coding region of the mouse Trem2 gene was replaced by the lacZ gene, followed by a floxed sequence containing a neomycin-resistance gene driven by the human Ubiquitin C promoter. This ectopic promoter was found to drive expression of the Treml1 gene, located approximately 8kb from the 3′ end of Trem2. Treml1 transcript levels in Trem2−/− mice are more than 300 times those of wild-type mice and protein levels are 19 times greater; these levels return to wild-type when the Ubiquitin C promoter-neor sequence is excised by crossing the Trem2−/− mice with mice expressing Cre recombinase (Kang et al., 2017). Because of uncertainty whether Treml1 overexpression obscures the impact of TREM2 deficiencies in Trem2−/− mice, it is recommended that the Ubiquitin C promoter-neor sequence be excised before using these mice to study the effects of TREM2 loss of function (Kang et al., 2017).
Characterization of this line has thus far been conducted using Trem2−/− mice that carry the Ubiquitin C promoter in the Trem2 locus, so any possible effects of Treml1 overexpression are unknown.
At six months of age, Trem2−/− mice perform similarly to wild-type mice in a variety of behavioral tests, including the open-field test, elevated plus maze, three-chamber social-interaction test, and contextual and cued fear-conditioning test (Kang et al., 2017). It remains to be seen whether there are age-dependent effects of Trem2 ablation.
There are differences in the transcriptomes of Trem2−/− and wild-type mice, both under basal conditions and 48 hours after systemic Lipopolysaccharide (LPS) administration, particularly in pathways involving inflammation and chemotaxis of immune cells. Among the transcripts that differ during basal conditions are Treml1, Ctsk, Mmp9, Lcn2, and S100a8; among those that differ during LPS challenge are Treml1, Avp, Ccl19, Acp5, and Mmp9 (Kang et al., 2017).
Microglia in Trem2−/− mice exhibit a muted response to neuronal injury: Trem2−/− microglia show less proliferative activity and less pronounced changes in morphology than do wild-type microglia after an excitotoxic insult (Zheng et al., 2017).
Microglia cultured from Trem2−/− mice show decreased proliferation and increased apoptosis compared with cells cultured from wild-type mice (Zheng et al., 2017).
The entire coding region of the Trem2 gene was replaced by Velocigene cassette ZEN-Ub1 (lacZ -p(A)-loxP-hUbCpro-neor-p(A)-loxP). Mice are maintained on a C57BL/6N background.
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
Changes in LTP/LTD
At six months, mice perform normally in the open-field test, elevated plus maze, three-chamber social-interaction test, and contextual and cued fear-conditioning test.
- Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet. 2002 Sep;71(3):656-62. Epub 2002 Jun 21 PubMed.
- Paloneva J, Autti T, Hakola P, Haltia MJ. Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL). In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 2002 Jan 24 [updated 2015 Mar 12].
- Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, Dursun B, Bilgic B, Hanagasi H, Gurvit H, Emre M, Singleton A, Hardy J. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 2013 Jan;70(1):78-84. PubMed.
- Guerreiro R, Bilgic B, Guven G, Brás J, Rohrer J, Lohmann E, Hanagasi H, Gurvit H, Emre M. Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiol Aging. 2013 Dec;34(12):2890.e1-5. Epub 2013 Jul 17 PubMed.
- Le Ber I, De Septenville A, Guerreiro R, Bras J, Camuzat A, Caroppo P, Lattante S, Couarch P, Kabashi E, Bouya-Ahmed K, Dubois B, Brice A. Homozygous TREM2 mutation in a family with atypical frontotemporal dementia. Neurobiol Aging. 2014 Oct;35(10):2419.e23-2419.e25. Epub 2014 Apr 18 PubMed.
- Jay TR, von Saucken VE, Landreth GE. TREM2 in Neurodegenerative Diseases. Mol Neurodegener. 2017 Aug 2;12(1):56. PubMed.
- Yeh FL, Hansen DV, Sheng M. TREM2, Microglia, and Neurodegenerative Diseases. Trends Mol Med. 2017 Jun;23(6):512-533. Epub 2017 Apr 22 PubMed.
- Kang SS, Kurti A, Baker KE, Liu CC, Colonna M, Ulrich JD, Holtzman DM, Bu G, Fryer JD. Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal. Hum Mol Genet. 2018 Jan 15;27(2):211-223. PubMed.
- Zheng H, Jia L, Liu CC, Rong Z, Zhong L, Yang L, Chen XF, Fryer JD, Wang X, Zhang YW, Xu H, Bu G. TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway. J Neurosci. 2017 Feb 15;37(7):1772-1784. Epub 2017 Jan 11 PubMed.
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