Genes: Mapt, MAPT, Trem2
Modification: Mapt: Knock-Out; MAPT: Transgenic; Trem2: Knock-Out
Disease Relevance: Nasu-Hakola Disease, Alzheimer's Disease, Frontotemporal Dementia
Strain Name: TREM2tm1(KOMP)Vlcg; B6.Cg-Mapttm1(EGFP)Klt Tg(MAPT)8cPdav/J
Genetic Background: C57BL/6
Availability: htau: The Jackson Lab: Stock# 005491, live. Trem2 KO: UC Davis KOMP Repository, Project VG10093, cryorecovery 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). Homozygous TREM2 mutations also have been associated with frontotemporal dementia in the absence of bone abnormalities (Chouery et al., 2008; 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).
hTau;Trem2−/− mice are useful for studying the effects of loss of TREM2 function in the context of wild-type human tau. These mice are the result of crossing htau mice, which express all six isoforms of the human tau protein under the control of the human MAPT promoter, but do not express mouse tau, and Trem2−/− mice. The Trem2-/- line 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. It should be noted that the Ubiquitin C promoter was found to drive over expression of the Treml1 gene, located approximately 8kb from the 3′ end of Trem2, and it is uncertain whether Treml1 overexpression obscures the impact of TREM2 deficiencies in Trem2−/− mice (Kang et al., 2017). It should also be noted that the genetic modification as described in the original manuscript is inaccurate (Jay et al., 2015).
Six-month-old hTau;Trem2−/− mice were used to investigate the influence of loss of TREM2 function on tau pathology and tauopathy-induced neuroinflammation (Bemiller et al., 2017).
Htau mice exhibit age-related tau pathology: tau hyperphosphorylation and mislocalization to cell bodies and dendrites are evident at three months, and the formation of insoluble tau aggregates is evident at six months. Levels of total tau in the cortex and hippocampus are similar in htau;Trem2+/+ and hTau;Trem2−/− mice. However, at six months of age, tau phosphorylation and aggregation in the cortex are augmented in mice lacking TREM2.
The number of Iba1-positve microglial cells and the levels of Iba1 transcripts in cortex and CA3 are also similar in six-month htau;Trem2+/+ and hTau;Trem2−/− mice. However there are pronounced differences in microglial morphology between htau;Trem2+/+ and hTau;Trem2−/− mice—microglia in mice lacking TREM2 are smaller, and their processes are thinner and less ramified.
Transcript levels of markers associated with neuroinflammation (IL-1β, iNOS, TNF-α, IL-6, TGF-β, RETNLB, ARG1, TLR4, or DAP12/TYROBP) do not differ between htau;Trem2+/+ and hTau;Trem2−/− mice.
At six months of age, levels of stress-related protein kinases (including total JNK, active pJNK/total JNK; total GSK3β, active pGSK3β(Y216)/total GSK3β; active pERK1/2/total ERK1/2) in cortex and hippocampus are greater in mice lacking TREM2. Differences in levels of stress-related kinases are also seen at three months of age in the hippocampus, but not the cortex, preceding differences in tau phosphorylation.
No differences in neurodegeneration, as assessed by NeuN immunoreactivity, are seen between htau;Trem2+/+ and hTau;Trem2−/− mice at six months of age. As neuron loss in htau mice reportedly begins between eight and 18 months of age (Androfer et al., 2005), it may be necessary to examine older animals in order to definitively determine whether lack of TREM2 influences neuron death.
Htau mice were bred to Trem2−/− mice (Trem2tm1(KOMP)Vlcg) to generate hTau;Trem2−/− and htau;Trem2+/+ mice. These mice were backcrossed for four generations, and maintained on a C57BL/6 background (Bemiller et al., 2017).
Trem2tm1(KOMP)Vlcg was generated by the NIH Knockout Mouse Project. 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.
Htau mice were generated by mating mice that expressed human MAPT (8c mice) (Duff et al., 2000), with tau knockout mice with a targeted disruption of exon 1 of Mapt (Tucker et al., 2001), then back-crossing to obtain mice homozygous for the disrupted murine Mapt while carrying the human MAPT transgene.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
- Cognitive Impairment
Neuron loss not observed in cortex or hippocampal field CA3 at 6 months of age; later ages were not studied.
Microgliosis observed by 6 months, younger ages were not studied.
Changes in LTP/LTD
Last Updated: 18 Jan 2018
Research Models Citations
- 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].
- Chouery E, Delague V, Bergougnoux A, Koussa S, Serre JL, Mégarbané A. Mutations in TREM2 lead to pure early-onset dementia without bone cysts. Hum Mutat. 2008 Sep;29(9):E194-204. PubMed.
- 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.
- Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, Xu G, Margevicius D, Karlo JC, Sousa GL, Cotleur AC, Butovsky O, Bekris L, Staugaitis SM, Leverenz JB, Pimplikar SW, Landreth GE, Howell GR, Ransohoff RM, Lamb BT. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med. 2015 Mar 9;212(3):287-95. Epub 2015 Mar 2 PubMed.
- Bemiller SM, McCray TJ, Allan K, Formica SV, Xu G, Wilson G, Kokiko-Cochran ON, Crish SD, Lasagna-Reeves CA, Ransohoff RM, Landreth GE, Lamb BT. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener. 2017 Oct 16;12(1):74. PubMed.
- Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci. 2005 Jun 1;25(22):5446-54. PubMed.
- Duff K, Knight H, Refolo LM, Sanders S, Yu X, Picciano M, Malester B, Hutton M, Adamson J, Goedert M, Burki K, Davies P. Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis. 2000 Apr;7(2):87-98. PubMed.
- Tucker KL, Meyer M, Barde YA. Neurotrophins are required for nerve growth during development. Nat Neurosci. 2001 Jan;4(1):29-37. PubMed.