Genes: Trem2, MAPT
Mutations: MAPT P301S
Modification: Trem2: Knock-Out; MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Alzheimer's Disease
Strain Name: C57BL/6 -TREM2tm1cln; B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J
Genetic Background: C57BL/6
Availability: Trem2 KO: available through Marco Colonna. PS19: The Jackson Lab: Stock# 008169; Live
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 (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).
To investigate the influence of loss of TREM2 function on tau pathology, tauopathy-induced neuroinflammation, and neurodegeneration, PS19 mice (Yoshiyama et al., 2007) were crossed with Trem2-/- mice (Turnbull et al., 2006). PS19 mice express human tau (1N4R) with the FTD-linked P301S mutation, and exhibit substantial neurofibrillary tangles, gliosis, and brain atrophy by nine months of age.
Characterization of Trem2-/-PS19 has thus far been reported for nine-month male mice (Leyns et al., 2017).
Trem2-/-PS19 and Trem2+/+PS19 mice do not obviously differ with regard to levels of phosphorylated or insoluble tau. Nonetheless, microglial activation is significantly diminished in Trem2-/-PS19 animals. Compared with Trem2+/+PS19 mice, Trem2-/-PS19 have fewer microglia in the piriform cortex, and microglial area is reduced in the cortex and hippocampus. Trem2-/-PS19 microglia have a ramified morphology, while Trem2+/+PS19 microglia have a more amoeboid shape characteristic of activated microglia. Expression of markers of microglial activation (Cst7 and Apoe), proinflammatory cytokines (IL-1β, IL-1α, TNF-α), and the complement cascade component C1q are all reduced in Trem2-/-PS19 mice compared with Trem2+/+PS19 mice. There is also less astrogliosis, evaluated in piriform cortex and hippocampus, in PS19 mice lacking TREM2.
Neurodegeneration is less severe in Trem2-/-PS19 mice than Trem2+/+PS19 animals. Shrinkage of entorhinal and piriform cortices and ventricular enlargement are attenuated in mice lacking TREM2. The two genotypes do not differ with regard to hippocampal volume. However, higher levels of the postsynaptic marker PSD95 in the hippocampus of Trem2-/-PS19 mice suggest less hippocampal synapse loss than in Trem2+/+PS19 animals.
Trem2-/-: Inactivation of the mouse Trem2 gene was achieved by targeted deletion of exons 3 and 4 (Turnbull et al., 2006).
PS19 transgenic mice express mutant human microtubule-associated protein tau, MAPT, driven by the mouse prion protein (Prnp) promoter. The transgene encodes the disease-associated P301S mutation and includes one N-terminal insert and four microtubule-binding domains (1N4R) (Yoshiyama et al., 2007).
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
Microgliosis and astrogliosis by 9 months (the earliest age studied).
Changes in LTP/LTD
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.
- Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 Feb 1;53(3):337-51. PubMed.
- Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L, Hernandez M, Colonna M. Cutting edge: TREM-2 attenuates macrophage activation. J Immunol. 2006 Sep 15;177(6):3520-4. PubMed.
- Leyns CE, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, Robinson GO, Anderson E, Colonna M, Holtzman DM. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11524-11529. Epub 2017 Oct 9 PubMed.