Genes: Trem2, APP, PSEN1
Mutations: APP KM670/671NL, APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V
Modification: Trem2: Knock-Out; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: C57BL/6 -TREM2tm1cln; B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmja
Genetic Background: C57BL/6
Availability: Trem2 KO: available through Marco Colonna. 5XFAD: The Jackson Lab; available through the JAX MMRRC Stock# 034848; 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 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).
To investigate the influence of loss of TREM2 function on amyloid pathology and plaque-associated neuroinflammation, 5XFAD mice were crossed with Trem2-/- mice (Turnbull et al., 2006). 5XFAD mice express human APP and human presenilin-1, with a total of five AD-linked mutations, and aggressively deposit amyloid plaques, starting at six weeks of age. Trem2-/- mice were generated by targeted deletion of Trem2 exons 3 and 4. All mice were on a C57BL/6 background (Ulland et al., 2017).
The numbers of microglia are similar in Trem2+/+5XFAD and Trem2-/-5XFAD at four months of age (Wang et al., 2016), but at eight months of age, Trem2-/-5XFAD have fewer total microglia (Wang et al., 2016) and an increased number of apoptotic microglia (Wang et al., 2015).
TREM2 insufficiency in 5XFAD mice leads to an altered microglial response to amyloid plaques, already apparent by four months. Compared with Trem2+/+5XFAD, significantly fewer microglia surround plaques in 5XFAD mice lacking or haploinsufficient for TREM2 (Wang et al., 2016). Microglial processes in Trem2+/+5XFAD orient toward and envelop plaques, and processes contacting plaques are enriched in phospho-tyrosine, a marker of kinase activation; microglia in Trem2-/-5XFAD and Trem2+/-5XFAD are less polarized, with dysmorphic processes that do not follow plaque borders and do not show evidence of kinase activation (Yuan et al., 2016). The failure of microglia to concentrate around plaques persists in eight-month Trem2-/-5XFAD and Trem2+/-5XFAD mice (Wang et al., 2015).
Microglia in eight-month Trem2-/-5XFAD mice contain abundant autophagosomes, rarely seen in Trem2+/+5XFAD (Ulland et al., 2017).
Microglia from Trem2-/-5XFAD have a transcriptional profile intermediate between Trem2+/+5XFAD and wild-type mice (Wang et al., 2015).
In vitro, microglia derived from Trem2-/-5XFAD mice are less viable than cells from Trem2+/+5XFAD (Wang et al., 2015).Trem2-/-5XFAD microglia less efficiently phagocytize Aβ than do microglia from Trem2+/+5XFAD or Trem2+/-5XFAD (Wang et al., 2016; Yuan et al., 2016).
At four months of age, Trem2+/+5XFAD, Trem2+/-5XFAD and Trem2-/-5XFAD mice do not differ in terms of total plaque burden or levels of insoluble Aβ40 and Aβ42 (Wang et al., 2016; Yuan et al., 2016). However, the decreased microglial coverage in mice lacking TREM2 is accompanied by changes in plaque morphology. While Thioflavin S-labeled plaques have distinct borders in Trem2+/+5XFAD, plaques inTREM2-deficient mice lack sharp borders and sport “spike-like” extensions. Trem2+/-5XFAD and Trem2-/-5XFAD also have a significantly larger proportion of filamentous plaques—Thioflavin S-labeled plaques without a discernible core—than do Trem2+/+5XFAD mice.
At eight months of age, Trem2-/-5XFAD have greater plaque burdens and elevated levels of insoluble Aβ40 and Aβ42 in the hippocampus, but not in cortex, compared with Trem2+/+5XFAD (Wang et al., 2015). The relative abundance of modified Aβ42 peptides (e.g., Aβp3-42) within plaques also differs between Trem2+/+5XFAD and 5XFAD deficient in TREM2 (Wang et al., 2016).
The loss of layer V neurons seen in 5XFAD mice (Oakley et al., 2006; Jawhar et al., 2012) is exaggerated in Trem2-/-5XFAD and Trem2+/-5XFAD animals, in a gene-dose-dependent manner (Wang et al., 2015). Plaque-associated neuritic dystrophy is more severe in Trem2-/-5XFAD than in Trem2+/+5XFAD (Wang et al., 2016; Yuan et al., 2016).
5XFAD mice were crossed with Trem2 KO (Colonna) mice. All mice were on a C57BL/6 background.
Trem2 KO (Colonna) x APPPS1 - The effects of TREM2 deficiency also have been studied in APPPS1 mice, which express human APP and PSEN1, with the AD-linked Swedish and L166P mutations, respectively. Trem2 haploinsufficiency had no effect on cortical plaque deposition in three- or seven-month mice (Ulrich et al., 2014), but Trem2-/-APPPS1mice had lower plaque burdens than APPPS1 mice, studied at four months of age (Krasemann et al., 2017). A reduction in microglial clustering around plaques was seen in APPPS1 mice deficient in TREM2, studied at three months of age (Ulrich et al., 2014; Wang et al., 2015). The microglia that did associate with neuritic plaques in Trem2-/-APPPS1 mice did not undergo the switch from a homeostatic to a “microglial neurodegenerative phenotype,” seen in microglia in APPPS1 mice that express Trem2 (Krasemann et al., 2017).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Synaptic Loss
- Changes in LTP/LTD
- Cognitive Impairment
Plaques present by 4 months, the earliest age studied.
Loss of cortical layer V neurons by 8 months, the earliest age studied.
MIcrogliosis by 4 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.
- 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.
- Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, Loboda AA, Zhou Y, Cairns NJ, Kambal A, Loginicheva E, Gilfillan S, Cella M, Virgin HW, Unanue ER, Wang Y, Artyomov MN, Holtzman DM, Colonna M. TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Cell. 2017 Aug 10;170(4):649-663.e13. PubMed.
- Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, Yuan P, Mahan TE, Shi Y, Gilfillan S, Cella M, Grutzendler J, DeMattos RB, Cirrito JR, Holtzman DM, Colonna M. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016 May 2;213(5):667-75. Epub 2016 Apr 18 PubMed.
- Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, Gilfillan S, Krishnan GM, Sudhakar S, Zinselmeyer BH, Holtzman DM, Cirrito JR, Colonna M. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015 Mar 12;160(6):1061-71. Epub 2015 Feb 26 PubMed.
- Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, Luo W, Colonna M, Baddeley D, Grutzendler J. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron. 2016 May 18;90(4):724-39. PubMed.
- Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006 Oct 4;26(40):10129-40. PubMed.
- Jawhar S, Trawicka A, Jenneckens C, Bayer TA, Wirths O. Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer's disease. Neurobiol Aging. 2012 Jan;33(1):196.e29-40. PubMed.
- Ulrich JD, Finn MB, Wang Y, Shen A, Mahan TE, Jiang H, Stewart FR, Piccio L, Colonna M, Holtzman DM. Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener. 2014 Jun 3;9:20. PubMed.
- Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017 Sep 19;47(3):566-581.e9. PubMed.
- Without TREM2, Microglia Run Out of Gas
- Microglial Regulation and Function Scrutinized at Heidelberg Meeting
- Hot DAM: Specific Microglia Engulf Plaques
- Barrier Function: TREM2 Helps Microglia to Compact Amyloid Plaques
- TREM2 Buoys Microglial Disaster Relief Efforts in AD and Stroke
- United in Confusion: TREM2 Puzzles Researchers in Taos
- TREM2 Mystery: Altered Microglia, No Effect on Plaques
- Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.