Boosting angiotensin-converting enzyme (ACE) in microglia protects against Alzheimer’s disease in 5xFAD mice
Open accessAbstract
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.
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Self-citation
- Authors
- Gomez, A. R., Byun, H. R., Wu, S., Muhammad, A. K. M. G., Ikbariyeh, J., Chen, J., Muro, A., Li, L., Bernstein, K. E., Ainsworth, R., & Tourtellotte, W. G.
- Affiliations
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Tourtellotte, Warren G.
- ORCID
- Venue
- Nature Aging
- Published
- 2025-06-09
- Volume
- 5
- Issue
- 7
- Pages
- 1280-1294
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC11071489
- OpenAlex
- W4411157508
- Cited by
- 13
- References
- 15
- Citations by year
- 2026: 10 · 2025: 2 · 2024: 1
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- green
- dx.doi.org
- Licence
- Locations
- Nature Aging (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1-AG-07365, R01-Ag074365)
- Cedars-Sinai Medical Center (Golcrich Alzheimer's Center Grant, Goldrich Alzheimer's Center Grant)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R01-AI164519)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- angiotensin-converting enzyme, microglia, Alzheimer's disease, amyloid plaques, amyloid-beta phagocytosis, endolysosomal trafficking, Syk, TREM2, Dectin-1, 5xFAD mice, cell therapy, innate immunity, learning and memory impairment
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