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Effects of microglial depletion and TREM2 deficiency on Aβ plaque burden and neuritic plaque tau pathology in 5XFAD mice
Delizannis AT, Nonneman A, Tsering W, De Bondt A, Van den Wyngaert I, Zhang B, Meymand E, Olufemi MF et al.. Acta neuropathologica communications, 2021-09-09
Topic: Brain proteins, microglia and lab models
Plain-language summary
Dystrophic neuronal processes harboring neuritic plaque (NP) tau pathology are found in association with Aβ plaques in Alzheimer's disease (AD) brain. Microglia are also in proximity to these plaques and microglial gene variants are known risk factors in AD, including loss-of-function variants of TREM2. We have further investigated the role of Aβ plaque-associated microglia in 5XFAD mice in which NP tau pathology forms after intracerebral injection of AD brain-derived pathologic tau (AD-tau), focusing on the consequences of reduced TREM2 expression and microglial depletion after treatment with the colony-stimulating factor 1 (CSFR1) inhibitor, PLX3397. Young 5XFAD mice treated with PLX3397 had a large reduction of brain microglia, including cortical plaque-associated microglia, with a significant reduction of Aβ plaque burden in the cortex. A corresponding decrease in cortical APP-positive dystrophic processes and NP tau pathology were observed after intracerebral AD-tau injection in the PLX3397-treated 5XFAD mice. Consistent with prior reports, 5XFAD × TREM2 -/- mice showed a significant reduction of plaque-associated microglial, whereas 5XFAD × TREM2 +/- mice had significantly more plaque-associated microglia than 5XFAD × TREM2 -/- mice. Nonetheless, AD-tau injected 5XFAD × TREM2 +/- mice showed greatly increased AT8-positive NP tau relative to 5XFAD × TREM2 +/+ mice. Expression profiling revealed that 5XFAD × TREM2 +/- mice had a disease-associated microglial (DAM) gene expression profile in the brain that was generally intermediate between 5XFAD × TREM2 +/+ and 5XFAD × TREM2 -/- mice. Microarray analysis revealed significant differences in cortical and hippocampal gene expression between AD-tau injected 5XFAD × TREM2 +/- and 5XFAD × TREM2 -/- mice, including pathways linked to microglial function. These data suggest there is not a simple correlation between the extent of microglia plaque interaction and plaque-associated neuritic damage. Moreover, the differences in gene expression and microglial phenotype between TREM2 +/- and TREM2 -/- mice suggest that the former may better model the single copy TREM2 variants associated with AD risk.
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APA 7th
Delizannis, A. T., Nonneman, A., Tsering, W., De Bondt, A., Van den Wyngaert, I., Zhang, B., et al. (2021). Effects of microglial depletion and TREM2 deficiency on Aβ plaque burden and neuritic plaque tau pathology in 5XFAD mice. Acta neuropathologica communications. https://doi.org/10.1186/s40478-021-01251-1
Vancouver
Delizannis AT, Nonneman A, Tsering W, De Bondt A, Van den Wyngaert I, Zhang B, et al. Effects of microglial depletion and TREM2 deficiency on Aβ plaque burden and neuritic plaque tau pathology in 5XFAD mice. Acta neuropathologica communications. 2021. doi:10.1186/s40478-021-01251-1. PMID: 34503586.
BibTeX
@article{delizannis2021-34503586,
author = {Delizannis, A. T. and Nonneman, A. and Tsering, W. and De Bondt, A. and Van den Wyngaert, I. and Zhang, B. and Meymand, E. and Olufemi, M. F. and others},
title = {{Effects of microglial depletion and TREM2 deficiency on Aβ plaque burden and neuritic plaque tau pathology in 5XFAD mice}},
journal = {Acta neuropathologica communications},
year = {2021},
doi = {10.1186/s40478-021-01251-1},
pmid = {34503586},
url = {https://doi.org/10.1186/s40478-021-01251-1}
}
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Key findings
- Young 5XFAD mice treated with PLX3397 had a large reduction of brain microglia, including cortical plaque-associated microglia, with a significant reduction of Aβ plaque burden in the cortex.
- Consistent with prior reports, 5XFAD × TREM2 -/- mice showed a significant reduction of plaque-associated microglial, whereas 5XFAD × TREM2 +/- mice had significantly more plaque-associated microglia than 5XFAD × TREM2 -/- mice.
- Expression profiling revealed that 5XFAD × TREM2 +/- mice had a disease-associated microglial (DAM) gene expression profile in the brain that was generally intermediate between 5XFAD × TREM2 +/+ and 5XFAD × TREM2 -/- mice.
- Microarray analysis revealed significant differences in cortical and hippocampal gene expression between AD-tau injected 5XFAD × TREM2 +/- and 5XFAD × TREM2 -/- mice, including pathways linked to microglial function.
- Moreover, the differences in gene expression and microglial phenotype between TREM2 +/- and TREM2 -/- mice suggest that the former may better model the single copy TREM2 variants associated with AD risk.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Acta neuropathologica communications) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “5xfad”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34503586) |
| Free to read | 2 / 2 | Free to read |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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