Species: Mouse
Genes: Trem2, APP, PSEN1
Mutations: APP K670_M671delinsNL (Swedish), PSEN1 L166P
Modification: Trem2: Knock-Out; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: TREM2^{tm1(KOMP)Vlcg}; B6.Cg-Tg(Thy1-APPSw,Thy1-PSEN1*L166P)21Jckr
Genetic Background: C57BL/6
Availability: APPPS1 available through Mathias Jucker; Trem2 KO available through UC Davis KOMP Repository, Project VG10093, cryo-recovery or sperm

Summary

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), and may confer increased risk for Alzheimer’s disease and other neurodegenerative disorders (Jay et al., 2017; Yeh et al., 2017).

To investigate the influence of loss of TREM2 function on amyloid pathology and plaque-associated neuroinflammation, APPPS1 mice were crossed with Trem2 KO (Trem2^-/-) mice (Jay et al., 2015; Jay et al., 2017). APPPS1 mice carry human transgenes for both APP bearing the Swedish mutation and PSEN1containing an L166P mutation. 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).

In APPPS1 mice, deletion of Trem2 resulted in a reduced number of myeloid cells surrounding amyloid plaques. (It should be noted that plaque-associated myeloid cells in APPPS1;Trem2^+/+ and APPPS1;Trem2^-/- were identified as peripheral monocytes that migrated into the brain, and not resident microglia, although this identification is controversial.) Myeloid cell proliferation in the cortex was reduced at eight months of age in APPPS1;Trem2^-/- compared with APPPS1;Trem2^+/+. Phagocytosis of Aβ by myeloid cells, assessed by co-localization of 6E10 and Iba1 immunoreactivity, was reduced in the brains of mice lacking TREM2 (Jay et al., 2017).

The number of plaque-associated reactive astrocytes was also reduced in APPPS1;Trem2^-/- brains compared with APPPS1;Trem2^+/+ (Jay et al., 2015; Jay et al., 2017).

The effects of Trem2 deletion on amyloid burden were found to be stage-dependent, ameliorating amyloid pathology at earlier stages of amyloid deposition but exacerbating pathology at later stages (Jay et al., 2015; Jay et al., 2017). At early stages of amyloid deposition— two months of age in cortex, four months in hippocampus—the area occupied by 6E10-immunoreactive plaques was less in APPPS1;Trem2^-/- mice compared with APPPS1;Trem2^+/+ animals. At middle stages—four months of age in cortex, eight months in hippocampus—the area occupied by 6E10-immunoreactive plaques did not differ between APPPS1;Trem2^-/- and APPPS1;Trem2^+/+ animals. Finally, at late stages—eight months of age in cortex—there was an increase in the 6E10-positive plaque area in mice lacking TREM2.

There was a reduction in phospho-tau immunoreactivity in dystrophic neurites surrounding plaques in APPPS1;Trem2^-/- compared with APPPS1;Trem2^+/+ brains, assessed at four months (Jay et al., 2015).

Modification Details

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.

APPPS1 mice express human APP with the Swedish (K670M/N671L) mutations and human PSEN1 with the L166P mutation, both under control of the Thy1 promoter (Radde et al., 2006). Mice are maintained on a C57BL/6 background.

Phenotype Characterization

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References

Research Models Citations

1. APPPS1
2. Trem2 KO (KOMP)

Paper Citations

1. 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.
2. 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].
3. Jay TR, von Saucken VE, Landreth GE. TREM2 in Neurodegenerative Diseases. Mol Neurodegener. 2017 Aug 2;12(1):56. PubMed.
4. 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.
5. 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.
6. Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, Lamb BT, Landreth GE. Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease. J Neurosci. 2017 Jan 18;37(3):637-647. PubMed.
7. 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.
8. Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jäggi F, Wolburg H, Gengler S, Haass C, Ghetti B, Czech C, Hölscher C, Mathews PM, Jucker M. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 2006 Sep;7(9):940-6. PubMed.

Other Citations

1. Mathias Jucker

External Citations

1. Trem2tm1(KOMP)Vlcg
2. UC Davis KOMP Repository, Project VG10093

Further Reading