Summary of microglia and TREM2 effects on tau-linked pathologies in animal models
| Condition . | . | Model . | Age . | Tau propagation and tau pathology . | Neurodegeneration . | Glial reactivity . | Aβ . | Reference . |
|---|---|---|---|---|---|---|---|---|
| Microglial depletion | Aβ models | 5xFAD × P301S + injection of recombinant tau seeds | 7 mo | ↓ AT8 area (CX, HC) | ↓ Neurodegeneration (CX, HC) | Remaining microglia exhibit DAM phenotype | No difference | Lodder et al. (2021) |
| AppNL-G-F+ AAV-P301L-tau injection | 6 mo | ↓ AT8 propagation ↑ AT8 plaque area | - | ↓ MGnD+ total and plaque area (Clec7a) | ↑ SP N ↑ SP areas ↑ SP size | Clayton et al. (2021) | ||
| 5xFAD + injection of AD brain–derived tau | 9.5 mo | ↑ AT8 seeding and propagation ↑ AT8 area (CX, HC) | - | No difference in microglial reactivity (CD68) No difference in astrocyte clustering around plaques ↑ GFAP RNA expression | No difference | Gratuze et al. (2021) | ||
| 5xFAD + injection of AD brain–derived tau | 6 mo | ↓ AT8 signal (CX) | - | - | ↓ SP load ↓ SP size | Delizannis et al. (2021) | ||
| Tau models | P301S | 4 mo | ↓ AT8 ↓ globular tau oligomers ↓ NFTs No difference in AT8 or T-tau (ELISA) | ↓ Neurodegeneration | ↓ Expression of proinflammatory cytokines | - | Mancuso et al. (2019) | |
| P301S × APOE4 KI or apoE KO | 9 mo | ↓ AT8 area (HC) ↓ HJ14.5 (pSer396) levels (CX) | ↓ Neurodegeneration (entorhinal/piriform CX, HC) | Remaining microglia exhibit reactive state (CD68) | - | Shi et al. (2019) | ||
| C57BL/6 + injection of AAV-GFP/tau | 4.5 mo | ↓ tau propagation (?) ↓ AT8+ cells (EC and DG) | - | - | - | Asai et al. (2015) | ||
| Tg4510 | 15 mo | No differences | No difference | Microglia exhibit DAM phenotype (e.g., apoE, CD68) No change in astrocyte reactivity (GFAP) | - | Bennett et al. (2018) | ||
| TREM2 depletion or R47H expression | Aβ models | APPPS1-21 × TREM2 KO Or TREM2 R47H + injection of AD brain–derived tau | 8.5 mo | ↑ AT8 seeding and propagation ↑ AT8 area (CX) ↑ AT8 signal near plaques | - | ↓ Microglial reactivity (Iba1) | ↑ Aβ42 in and around SP (CX) | Leyns et al. (2019) |
| 5xFAD + injection of AD brain–derived tau | 9 mo | ↑ AT8 seeding and propagation ↑ AT8 area (CX, HC) | - | ↓ Microglial reactivity (Iba1) ↓ Astrocytic reactivity (GFAP) | ↑ SP coverage (CX, HC) | Gratuze et al. (2021) | ||
| Tau models | P301S + TREM2 shRNA injection | 7 mo | ↑ AT8, AT100, and AT180 | ↑ Neurodegeneration (CX, HC) | ↑ Expression of proinflammatory cytokines | - | Jiang et al. (2015) | |
| htau × TREM2 KO | 6 mo | ↑ AT8 (CX, HC) ↑ AT180, PHF-1 (CX) | - | - | - | Bemiller et al. (2017) | ||
| P301S × TREM2 KO or TREM2 haploinsufficient mice | 8–9 mo | ↑ AT8 area (CX of haploinsufficient mice) ↑ MC1 area (HC of haploinsufficient mice) No difference in TREM2 KO mice | ↓ Neurodegeneration (ventricle area) | ↑ Microglial reactivity (based on morphology in haploinsufficient mice) TREM2 KO microglial morphology similar to WT | - | Sayed et al. (2018) | ||
| THY-Tau22 × TREM2 KO | 12 mo | ↑ AT8 (HC) ↑ N° of AT100+ and Gallyas+ neurons | ↓ Neurodegeneration (surface CA1) No difference in pyramidal nucleus layer thickness | ↓ Microglial reactivity (e.g., CD68, IL-1β) No difference in astrocyte reactivity (GFAP) | - | Vautheny et al. (2021) | ||
| AAV-P301L tau injection | 5 mo | ↑ tau spreading | - | ↑ Microglial reactivity (e.g., CD68, Clec7a, CD9 in DG) ↑ Microglial reactivity in MEC (CD9) | - | Zhu et al. (2022) | ||
| P301S x R47H | 9 mo | ↓ AT8 and PG5 area (HC) ↓ AT180 area (piriform CX) | ↓ Neurodegeneration (HC, entorhinal, piriform CX, pyramidal and DG layer thickness, ventricle volume) | ↓ Microglial reactivity (Iba1, CD68) ↓ DAM gene expression ↓ Proinflammatory cytokines | - | Gratuze et al. (2020) | ||
| TREM2 KO + injection of AD brain–derived tau | 9 mo | ↓ AT8 area No difference in HC | - | ↓ Microglial reactivity (Iba1) ↓ Neuroinflammatory response No change in astrocyte reactivity (GFAP) | - | Lee-Gosselin et al. (2023) | ||
| P301S × TREM2 KO | 9 mo | No difference | ↓ Neurodegeneration (entorhinal, piriform CX, ventricle volume) | ↓ Microglial reactivity (Iba1) ↓ Inflammatory markers Reduced astrocytic reactivity (GFAP) | - | Leyns et al. (2017) | ||
| TREM2R47H/TYROBP (Drosophila melanogaster) | 7 d | No difference | No difference | ↓ Inflammatory response | - | Sekiya et al. (2018) | ||
| TREM2 overexpression | P301S + lentiviral-mediated TREM2 overexpression | 7 mo | ↓ AT8 and AT180 (CX, HC) | ↓ Neurodegeneration (CX, HC) | ↓ Proinflammatory cytokines ↑ Anti-inflammatory markers | - | Jiang et al. (2016) |
| Condition . | . | Model . | Age . | Tau propagation and tau pathology . | Neurodegeneration . | Glial reactivity . | Aβ . | Reference . |
|---|---|---|---|---|---|---|---|---|
| Microglial depletion | Aβ models | 5xFAD × P301S + injection of recombinant tau seeds | 7 mo | ↓ AT8 area (CX, HC) | ↓ Neurodegeneration (CX, HC) | Remaining microglia exhibit DAM phenotype | No difference | Lodder et al. (2021) |
| AppNL-G-F+ AAV-P301L-tau injection | 6 mo | ↓ AT8 propagation ↑ AT8 plaque area | - | ↓ MGnD+ total and plaque area (Clec7a) | ↑ SP N ↑ SP areas ↑ SP size | Clayton et al. (2021) | ||
| 5xFAD + injection of AD brain–derived tau | 9.5 mo | ↑ AT8 seeding and propagation ↑ AT8 area (CX, HC) | - | No difference in microglial reactivity (CD68) No difference in astrocyte clustering around plaques ↑ GFAP RNA expression | No difference | Gratuze et al. (2021) | ||
| 5xFAD + injection of AD brain–derived tau | 6 mo | ↓ AT8 signal (CX) | - | - | ↓ SP load ↓ SP size | Delizannis et al. (2021) | ||
| Tau models | P301S | 4 mo | ↓ AT8 ↓ globular tau oligomers ↓ NFTs No difference in AT8 or T-tau (ELISA) | ↓ Neurodegeneration | ↓ Expression of proinflammatory cytokines | - | Mancuso et al. (2019) | |
| P301S × APOE4 KI or apoE KO | 9 mo | ↓ AT8 area (HC) ↓ HJ14.5 (pSer396) levels (CX) | ↓ Neurodegeneration (entorhinal/piriform CX, HC) | Remaining microglia exhibit reactive state (CD68) | - | Shi et al. (2019) | ||
| C57BL/6 + injection of AAV-GFP/tau | 4.5 mo | ↓ tau propagation (?) ↓ AT8+ cells (EC and DG) | - | - | - | Asai et al. (2015) | ||
| Tg4510 | 15 mo | No differences | No difference | Microglia exhibit DAM phenotype (e.g., apoE, CD68) No change in astrocyte reactivity (GFAP) | - | Bennett et al. (2018) | ||
| TREM2 depletion or R47H expression | Aβ models | APPPS1-21 × TREM2 KO Or TREM2 R47H + injection of AD brain–derived tau | 8.5 mo | ↑ AT8 seeding and propagation ↑ AT8 area (CX) ↑ AT8 signal near plaques | - | ↓ Microglial reactivity (Iba1) | ↑ Aβ42 in and around SP (CX) | Leyns et al. (2019) |
| 5xFAD + injection of AD brain–derived tau | 9 mo | ↑ AT8 seeding and propagation ↑ AT8 area (CX, HC) | - | ↓ Microglial reactivity (Iba1) ↓ Astrocytic reactivity (GFAP) | ↑ SP coverage (CX, HC) | Gratuze et al. (2021) | ||
| Tau models | P301S + TREM2 shRNA injection | 7 mo | ↑ AT8, AT100, and AT180 | ↑ Neurodegeneration (CX, HC) | ↑ Expression of proinflammatory cytokines | - | Jiang et al. (2015) | |
| htau × TREM2 KO | 6 mo | ↑ AT8 (CX, HC) ↑ AT180, PHF-1 (CX) | - | - | - | Bemiller et al. (2017) | ||
| P301S × TREM2 KO or TREM2 haploinsufficient mice | 8–9 mo | ↑ AT8 area (CX of haploinsufficient mice) ↑ MC1 area (HC of haploinsufficient mice) No difference in TREM2 KO mice | ↓ Neurodegeneration (ventricle area) | ↑ Microglial reactivity (based on morphology in haploinsufficient mice) TREM2 KO microglial morphology similar to WT | - | Sayed et al. (2018) | ||
| THY-Tau22 × TREM2 KO | 12 mo | ↑ AT8 (HC) ↑ N° of AT100+ and Gallyas+ neurons | ↓ Neurodegeneration (surface CA1) No difference in pyramidal nucleus layer thickness | ↓ Microglial reactivity (e.g., CD68, IL-1β) No difference in astrocyte reactivity (GFAP) | - | Vautheny et al. (2021) | ||
| AAV-P301L tau injection | 5 mo | ↑ tau spreading | - | ↑ Microglial reactivity (e.g., CD68, Clec7a, CD9 in DG) ↑ Microglial reactivity in MEC (CD9) | - | Zhu et al. (2022) | ||
| P301S x R47H | 9 mo | ↓ AT8 and PG5 area (HC) ↓ AT180 area (piriform CX) | ↓ Neurodegeneration (HC, entorhinal, piriform CX, pyramidal and DG layer thickness, ventricle volume) | ↓ Microglial reactivity (Iba1, CD68) ↓ DAM gene expression ↓ Proinflammatory cytokines | - | Gratuze et al. (2020) | ||
| TREM2 KO + injection of AD brain–derived tau | 9 mo | ↓ AT8 area No difference in HC | - | ↓ Microglial reactivity (Iba1) ↓ Neuroinflammatory response No change in astrocyte reactivity (GFAP) | - | Lee-Gosselin et al. (2023) | ||
| P301S × TREM2 KO | 9 mo | No difference | ↓ Neurodegeneration (entorhinal, piriform CX, ventricle volume) | ↓ Microglial reactivity (Iba1) ↓ Inflammatory markers Reduced astrocytic reactivity (GFAP) | - | Leyns et al. (2017) | ||
| TREM2R47H/TYROBP (Drosophila melanogaster) | 7 d | No difference | No difference | ↓ Inflammatory response | - | Sekiya et al. (2018) | ||
| TREM2 overexpression | P301S + lentiviral-mediated TREM2 overexpression | 7 mo | ↓ AT8 and AT180 (CX, HC) | ↓ Neurodegeneration (CX, HC) | ↓ Proinflammatory cytokines ↑ Anti-inflammatory markers | - | Jiang et al. (2016) |
CX: cortex; HC: hippocampus; GFAP: Glial Fibrillary Acidic Protein; SP: senile plaque; EC: entorhinal cortex; DG: dentate gyrus.