Genes: MAPT, TREM2, Trem2
Mutations: MAPT P301S, TREM2 R47H
Modification: MAPT: Transgenic; TREM2: Transgenic; Trem2: Knock-Out
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: N/A
Genetic Background: C57BL/6
Availability: PS19 mice are available from The Jackson Laboratory (Stock# 008169). TREM2 mice are available through Marco Colonna.
People who carry one copy of the R47H variant of TREM2 have an approximately threefold greater risk of developing Alzheimer’s disease than do people homozygous for the common variant. Earlier mouse models were generated to explore the effects of the R47H mutation in the context of amyloidosis (TREM2, humanized (R47H) X 5XFAD; Trem2 R47H KI (Lamb/Landreth) X APPPS1-21). This model, referred to here as PS19-TREM2R47H, was developed to examine the effects of the R47H mutation in the context of tauopathy (Gratuze et al., 2020). PS19-TREM2R47H mice carry transgenes encoding human MAPT with the P301S mutation linked to frontotemporal dementia and human TREM2-R47H, on a mouse-Trem2-null background. A second line, PS19-TREM2CV, carrying the common variant of TREM2 along with MAPT-P301S, was created to serve as a control. Compared with PS19 mice carrying the common variant of TREM2, mice carrying the R47H variant exhibited less tau pathology, brain atrophy, glial activation, and synapse loss.
Mice were characterized at 3 months, an age before the appearance of tau pathology in the parental PS19 line, and 9 months, a time when the parental line exhibits neurofibrillary tangles and brain atrophy. Only males were used in the initial study.
Tau pathology, assessed immunohistochemically, was attenuated in the hippocampi of PS19-TREM2R47H mice, compared with PS19-TREM2CV. This difference was already apparent at 3 months of age, using monoclonal antibody AT8, which recognizes tau phosphorylated at serine 202 and threonine 205. By 9 months, the genotypes also differed with regard to hippocampal levels of tau phosphorylated at serine 409 (revealed using antibody PG5), and there was also less staining in the piriform cortices of PS19-TREM2R47H mice, using antibody AT180, which detects tau phosphorylated at threonine 231.
Levels of total human tau in the hippocampus, measured by ELISA, did not differ between the genotypes at 3 months, but more tau was found in 9-month-old PS19-TREM2R47H than in PS19-TREM2CV.
At 3 months of age, brain volumes did not differ between PS19-TREM2R47H and PS19-TREM2CV animals. At 9 months, there were pronounced differences between the genotypes: The volumes of the hippocampus and piriform/entorhinal cortex were greater in carriers of the R47H variant. At the cellular level, the dentate gyrus and the pyramidal cell layer of the piriform cortex were thicker in the mutation carriers.
At 9 months of age, markers of glial reactivity were attenuated in mice carrying the R47H variant, compared with mice carrying the common variant of human TREM2. Expression of the astrocyte marker glial fibrillary acidic protein (GFAP) was decreased in R47H carriers, as was expression of the microglial marker Iba1. Other markers of microglial activation that differed between the genotypes include CD68 (cluster of differentiation 68), a marker of phagolysosomal activity, disease-associated microglia (DAM) genes, and pro-inflammatory cytokines (IL1α, IL1β, TNFα ,and TGFβ).
Synaptic integrity was preserved in PS19-TREM2R47H brains, compared with PS19-TREM2CV. The number of intact synapses, measured in the piriform cortex using the SEQUIN technique (see Jun 2020 news), was approximately 25 percent greater in R47H carriers, and electron microscopy revealed fewer dystrophic synapses.
There also appeared to be less phagocytosis of synapses by microglia in the brains of R47H carriers, as well as lower levels of C1q, a component of the classical complement cascade that tags synapses for elimination by microglia (Hong et al., 2016; see also April 2016 news).
Trem2-/-PS19 mice (PS19 mice lacking endogenous mouse Trem2) were generated by back-crossing PS19 mice (The Jackson Laboratory, Catalog# 008169) to Trem2-/- mice (Turnbull et al., 2006). During the course of these crosses, animals were moved onto a C57BL/6 genetic background.
Trem2-/-PS19 mice were then crossed with transgenic mice that carry a BAC encoding the R47H variant of human TREM2, as well as TREML1 and TREML2, on a Trem2 knockout background.
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
Tangles revealed using antibody PG5 at 9 months.
No data relative to wild-type mice, but at 9 months of age, the volumes of the hippocampus and entorhinal/piriform cortex are larger, and the granule cell layer of the dentate gyrus and pyramidal cell layer of the piriform cortex are thicker, in PS19-TREM2R47H mice, compared with PS19 mice carrying the common variant of human TREM2.
At 9 months of age, decreased expression of markers of astroglial and microglial reactivity, compared with PS19 mice carrying the common variant of TREM2, but no data relative to wild-type mice.
At 9 months of age, more synapses and fewer dystrophic synapses, compared with PS19 mice carrying the common variant of TREM2, but no data relative to wild-type mice.
Changes in LTP/LTD
Last Updated: 14 Jul 2020
Research Models Citations
- TREM2, humanized (R47H) X 5XFAD
- Trem2 R47H KI (Lamb/Landreth) X APPPS1-21
- PS19 with humanized TREM2 (common variant)
- Trem2 KO (Colonna) x PS19
- Tau P301S (Line PS19)
- Trem2 KO (Colonna)
- TREM2, humanized (R47H)
- Shiny SEQUIN: New Technique Counts Synapses Over Large Brain Volumes
- Paper Alert: Microglia Mediate Synaptic Loss in Early Alzheimer’s Disease
- Gratuze M, Leyns CE, Sauerbeck AD, St-Pierre MK, Xiong M, Kim N, Serrano JR, Tremblay MÈ, Kummer TT, Colonna M, Ulrich JD, Holtzman DM. Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration. J Clin Invest. 2020 Sep 1;130(9):4954-4968. PubMed.
- Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 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.