Genes: Trem2, APP, PSEN1
Mutations: TREM2 R47H, APP K670_M671delinsNL (Swedish), PSEN1 L166P
Modification: Trem2: Knock-In; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL6/J
Availability: Trem2+/R47H available through Gary Landreth or Bruce Lamb; APPPS1-21 available through Mathias Jucker.
R47H is a rare variant in TREM2 that triples the risk of Alzheimer’s disease in heterozygous carriers of this variant. In order to study the effects of R47H TREM2 in the context of amyloidosis, Trem2+/R47H mice were crossed with APPPS1-21 mice (Cheng-Hathaway et al., 2018). Trem2+/R47H mice have the R47H variant knocked into the endogenous mouse Trem2 gene, and APPPS1-21 mice express human APP with the Swedish mutation and human PSEN1 with the L166P mutation.
APPPS1-21;Trem2+/R47H mice have been characterized at four months of age. For comparison, APPPS1-21 mice were also crossed with Trem2 knockout mice (Trem2-/-), to generate APPPS1-21 mice haploinsufficient for Trem2 (APPPS1-21;Trem2+/-).
Levels of Trem2 transcripts were reduced in APPPS1-21;Trem2+/R47H compared with APPPS1-21;Trem2+/+ (by 64 percent in the hippocampus) and were similar to those in APPPS1-21 mice haploinsufficient for Trem2.
There is controversy as to whether the plaque-associated phagocytic cells in this model are resident microglia or peripherally derived macrophages (Jay et al., 2015; Wang et al., 2016); “myeloid cell” is used here to be consistent with the terminology of Cheng-Hathaway et al., 2018. Myeloid cells surround amyloid plaques in APPPS1-21 mice, and introduction of the R47H point mutation reduces clustering of myeloid cells around plaques, to a degree similar to that seen in APPPS1-21 mice haploinsufficient for Trem2 (approximately 40 percent reduction in the number of cells). Proliferation of myeloid cells was also reduced to a similar degree (approximately 30 percent) in APPPS1-21;Trem2+/R47H and APPPS1-21;Trem2+/− brains, compared with APPPS1-21;Trem2+/+ brains.
The R47H mutation had no effect on total plaque number or burden in the cortex and the hippocampus. However, there was a one-third reduction in the number and burden of fibrillar (Thioflavin S-positive) plaques in the hippocampus of APPPS1-21;Trem2+/R47H mice compared with APPPS1-21;Trem2+/+ mice. There was not an effect of genotype on plaque deposition in the cortices of four-month-old mice. Plaque deposition in the hippocampi lags behind deposition in the cortices in APPPS1-21 mice, and it has been shown previously that TREM2 deficiency results in less-severe plaque pathology at early stages of plaque deposition but in more-severe plaque pathology at later stages (Jay et al., 2015; Jay et al., 2017; Wang et al., 2015; Wang et al., 2016). The level of soluble Aβ40 in the cortices of APPPS1-21;Trem2+/R47H was lower than that in APPPS1-21;Trem2+/+ mice, resulting in a higher Aβ42/Aβ40 ratio in the animals carrying the R47H variant.
More severe plaque-associated neuritic dystrophy occurred in mice carrying the R47H variant than in mice homozygous for wild-type Trem2, again mimicking the effects of TREM2 deficiency.
Changes in the expression of inflammation-related genes, relative to APPPS1-21;Trem2+/+, are generally similar in APPPS1-21;Trem2+/R47H and APPPS1-21;Trem2+/− brains. However, there are some differences between the latter two genotypes—in the cortex, levels of Arg1, Fizz1, Ym1 and IL-6 are increased in APPPS1-21;Trem2+/R47H but not APPPS1-21;Trem2+/−—indicating that R47H heterozygosity does not completely phenocopy Trem2 haploinsufficiency.
Trem2+/R47H. CRISPR/Cas9 was used to introduce the R47H variant into the endogenous mouse Trem2 gene. No off-target mutations were identified by whole-genome sequencing in the founder lines used in the crosses described here.
APPPS1-21. APPPS1-21 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).
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
Reduction in the number and burden of fibrillar amyloid plaques in the hippocampus, compared with APPPS1-21 mice homozygous for wild-type Trem2.
Tangles were not observed at 4 months of age, but hyperphosphorylated tau was detected in dystrophic neurites surrounding plaques.
No differences in neuron number in cotical layer V in APPPS1-21;Trem2+/R47H mice relative to APPPS1-21 mice homozygous for wild-type Trem2, at 4 months of age.
Fewer plaque-associated myeloid cells in APPPS1-21;Trem2+/R47H, compared with APPPS1-21 mice homozygous for wild-type Trem2.
Changes in LTP/LTD
Last Updated: 03 Aug 2018
Research Models Citations
- Cheng-Hathaway PJ, Reed-Geaghan EG, Jay TR, Casali BT, Bemiller SM, Puntambekar SS, von Saucken VE, Williams RY, Karlo JC, Moutinho M, Xu G, Ransohoff RM, Lamb BT, Landreth GE. The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. Mol Neurodegener. 2018 Jun 1;13(1):29. 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.
- 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.
- 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.
- 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.
- 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.
No Available Further Reading