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Boosting angiotensin-converting enzyme (ACE) in microglia protects against Alzheimer's disease in 5xFAD mice
Andrew R Gomez, Hyae Ran Byun, Shaogen Wu, A K M Ghulam Muhammad, Jasmine Ikbariyeh, Jaelin Chen, Alek Muro, Lin Li et al.. Nature aging, 2025-06-09
Topic: Inflammation, microglia and astrocytes
Genome-wide association studies have identified many gene polymorphisms associated with an increased risk of developing late-onset Alzheimer's disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing innate immune responses and lipid metabolism of microglia (MG). Here we show that boosting the expression of angiotensin-converting enzyme (ACE), a genome-wide association study LOAD risk-associated gene product, specifically in MG, reduces amyloid-β (Aβ) plaque load, preserves vulnerable neurons and excitatory synapses, and significantly reduces learning and memory abnormalities in the 5xFAD amyloid mouse model of AD. ACE-expressing MG surround plaques more frequently and they have increased Aβ phagocytosis, endolysosomal trafficking and spleen tyrosine kinase activation downstream of the major Aβ receptors, triggering receptor expressed on myeloid cells 2 (Trem2) and C-type lectin domain family 7 member A (Clec7a). These findings establish a role for ACE in enhancing microglial immune function and they identify a potential use for ACE-expressing MG as a cell-based therapy to augment endogenous microglial responses to Aβ in AD.
Key findings
- Genome-wide association studies have identified many gene polymorphisms associated with an increased risk of developing late-onset Alzheimer's disease (LOAD).
- Here we show that boosting the expression of angiotensin-converting enzyme (ACE), a genome-wide association study LOAD risk-associated gene product, specifically in MG, reduces amyloid-β (Aβ) plaque load, preserves vulnerable neurons and excitatory synapses, and significantly reduces learning and memory abnormalities in the 5xFAD amyloid mouse model of AD.
- These findings establish a role for ACE in enhancing microglial immune function and they identify a potential use for ACE-expressing MG as a cell-based therapy to augment endogenous microglial responses to Aβ in AD.
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Study details
- Evidence strengthLow
How this study scored 46/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported and randomised / 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, multi-centre collaboration and free to read, so those were left out: it earned 26 of the 56 points we could judge it on, which is 46 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature aging) |
| 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 | 4 / 5 | 2025 — within 3 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 |
| Randomised / blinded | 0 / 2 | No randomisation 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 |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40490625) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 26 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 26 of the 56 points we could judge it on is 46 out of 100. |
| Total | 46 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Gomez, A. R., Byun, H. R., Wu, S., Muhammad, A. K. M. G., Ikbariyeh, J., Chen, J., et al. (2025). Boosting angiotensin-converting enzyme (ACE) in microglia protects against Alzheimer's disease in 5xFAD mice. Nature aging. https://doi.org/10.1038/s43587-025-00879-1
Vancouver
Gomez AR, Byun HR, Wu S, Muhammad AKMG, Ikbariyeh J, Chen J, et al. Boosting angiotensin-converting enzyme (ACE) in microglia protects against Alzheimer's disease in 5xFAD mice. Nature aging. 2025. doi:10.1038/s43587-025-00879-1. PMID: 40490625.
BibTeX
@article{gomez2025-40490625,
author = {Gomez, Andrew R and Byun, Hyae Ran and Wu, Shaogen and Muhammad, A K M Ghulam and Ikbariyeh, Jasmine and Chen, Jaelin and Muro, Alek and Li, Lin and others},
title = {{Boosting angiotensin-converting enzyme (ACE) in microglia protects against Alzheimer's disease in 5xFAD mice}},
journal = {Nature aging},
year = {2025},
doi = {10.1038/s43587-025-00879-1},
pmid = {40490625},
url = {https://doi.org/10.1038/s43587-025-00879-1}
}
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