Mutations: TREM2 T66M
Modification: Trem2: Knock-In
Disease Relevance: Frontotemporal Dementia
Strain Name: Trem2em1Bwef
Genetic Background: Mixed DBA/2J, FVB/ N, C57BL/6J
Availability: Available through Christian Haass
Loss-of-function mutations in TREM2 are associated with Nasu-Hakola disease, Alzheimer’s disease, and frontotemporal dementia (Yeh et al., 2017; Jay et al., 2017). At least three patients presenting with frontotemporal dementia-like symptoms have been found to be homozygous carriers of the TREM2 T66M variant (Guerreiro et al., 2013; LaBer et al., 2014). To study the effects of the T66M variant in vivo, the Trem2 T66M mouse was created, using CRISPR/Cas9 genome editing to introduce a CA>TG substitution directly into the murine Trem2 gene (Kleinberger et al., 2017).
Trem2 T66M homozygous and heterozygous mice express Trem2 transcripts at endogenous levels. Mice are fertile, reproduce with a normal Mendelian pattern of inheritance, and display normal mortality, at least to 19 months of age.
Trem2 T66M mice show a gene-dose-dependent accumulation of immature (not fully glycosylated) TREM2 protein in brain. There is also a gene-dose-dependent decrease in soluble TREM2 (sTREM2) in brain extracts, serum, and CSF of Trem2 T66M mice, paralleling the changes in sTREM2 in CSF of human heterozygous or homozygous carriers of the T66M variant (Piccio et al, 2016; Kleinberger et al, 2014; Henjum et al, 2016).
In vivo imaging using the PET tracer 18F-TSPO and Iba1 immunohistochemistry provide evidence of reduced microglial activation in the brains of homozygous Trem2 T66M mice. While cerebral TSPO PET signals increased between three and 12 months in wild-type mice, signals plateaued between five and eight months in Trem2 T66M mice and declined thereafter. Similarly, there is an age-dependent increase in Iba1 immunoreactivity in wild-type mice, which is not seen in Trem2 T66M mice. In particular, wild-type mice show an age-dependent accumulation of clusters of Iba1-immunoreactive microglia, which may be involved in removing axonal debris; these clusters were rarely seen in homozygous Trem2 T66M mice.
Additional in vivo imaging revealed reduced brain glucose metabolism (fluoro-2-deoxy- D-glucose µPET) at 12 months and reduced cerebral blood flow (continuous arterial spin-labeled magnetic resonance imaging) at six months in Trem2 T66M homozygotes, compared to wild-type mice. In 12-month homozygous Trem2 T66M mice, TSPO and FDG PET signals positively correlated, suggesting a relationship between reduced microglial activity and reduced glucose metabolism. Brain volumes in homozygous Trem2 T66M mice did not differ from those of wild-type mice, as measured by volumetric MRI.
Trem2 T66M mice show an exaggerated inflammatory response to lipopolysaccharide (LPS) stimulation. Intraperitoneal injection of LPS led to downregulation of Trem2 expression in both wild-type and Trem2 T66M mice, and to significantly increased levels of pro-inflammatory cytokines in brain and plasma of Trem2 T66M but not wild-type mice during the resolution phase of the inflammatory response.
Bone marrow-derived macrophages from heterozygous and homozygous Trem2 T66M mice show reduced proliferation, survival, and phagocytosis, compared with cells from wild-type mice, consistent with loss of TREM2 function in the T66M carriers.
A CA>TG substitution was introduced into the murine Trem2 gene using CRISPR/Cas9 genome editing. At the same time, two silent mutations were also introduced into the gene to allow genotyping by restriction enzyme digestion. Genome modification was performed in embryos derived from a D2B6F1 X FVB/N cross. Resulting mice were then back-crossed to C57BL/6J.
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
- 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.
- Jay TR, von Saucken VE, Landreth GE. TREM2 in Neurodegenerative Diseases. Mol Neurodegener. 2017 Aug 2;12(1):56. 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.
- 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.
- Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X, Focke C, Deußing M, Suárez-Calvet M, Mazaheri F, Parhizkar S, Pettkus N, Wurst W, Feederle R, Bartenstein P, Mueggler T, Arzberger T, Knuesel I, Rominger A, Haass C. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017 Jul 3;36(13):1837-1853. Epub 2017 May 30 PubMed.
- Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016 Jun;131(6):925-33. Epub 2016 Jan 11 PubMed.
- Kleinberger G, Yamanishi Y, Suárez-Calvet M, Czirr E, Lohmann E, Cuyvers E, Struyfs H, Pettkus N, Wenninger-Weinzierl A, Mazaheri F, Tahirovic S, Lleó A, Alcolea D, Fortea J, Willem M, Lammich S, Molinuevo JL, Sánchez-Valle R, Antonell A, Ramirez A, Heneka MT, Sleegers K, van der Zee J, Martin JJ, Engelborghs S, Demirtas-Tatlidede A, Zetterberg H, Van Broeckhoven C, Gurvit H, Wyss-Coray T, Hardy J, Colonna M, Haass C. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. PubMed.
- Henjum K, Almdahl IS, Årskog V, Minthon L, Hansson O, Fladby T, Nilsson LN. Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease. Alzheimers Res Ther. 2016 Apr 27;8(1):17. PubMed.