Aspirin-Triggered Lipoxin A4 Stimulates Alternative Activation of Microglia and Reduces Alzheimer Disease–Like Pathology in Mice
Open accessAbstract
Microglia play an essential role in innate immunity, homeostasis, and neurotropic support in the central nervous system. In Alzheimer disease (AD), these cells may affect disease progression by modulating the buildup of β-amyloid (Aβ) or releasing proinflammatory cytokines and neurotoxic substances. Discovering agents capable of increasing Aβ uptake by phagocytic cells is of potential therapeutic interest for AD. Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory properties directly involved in inflammatory resolution, an active process essential for appropriate host responses, tissue protection, and the return to homeostasis. Herein, we demonstrate that aspirin-triggered LXA4 (15 μg/kg) s.c., twice a day, reduced NF-κB activation and levels of proinflammatory cytokines and chemokines, as well as increased levels of anti-inflammatory IL-10 and transforming growth factor-β. Such changes in the cerebral milieu resulted in recruitment of microglia in an alternative phenotype, as characterized by the up-regulation of YM1 and arginase-1 and the down-regulation of inducible nitric oxide synthase expression. Microglia in an alternative phenotype-positive cells demonstrated improved phagocytic function, promoting clearance of Aβ deposits and ultimately leading to reduction in synaptotoxicity and improvement in cognition. Our data indicate that activating LXA4 signaling may represent a novel therapeutic approach for AD.
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Deficiency of FPR2 or administration of its inhibitors/anti-inflammatory ligands alleviates pathological symptoms of AD, including reduced activation of glial cells and tau hyperphosphorylation, and ultimately improves cognitive function.
“Deficiency of FPR2 or administration of its inhibitors/anti-inflammatory ligands could alleviate the pathological symptoms of AD, including reduced activation of glial cells (microglia and/or astrocytes) and tau hyperphosphorylation, and ultimately leading to improvement in cognitive function [151–154].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [151]
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- Authors
- Medeiros, R., Kitazawa, M., Passos, G. F., Baglietto-Vargas, D., Cheng, D., Cribbs, D. H., & LaFerla, F. M.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- LaFerla, Frank M.
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 182
- Issue
- 5
- Pages
- 1780-1789
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC3644736
- OpenAlex
- W2171245653
- Cited by
- 163
- References
- 60
- Citations by year
- 2025: 3 · 2024: 13 · 2023: 10 · 2022: 17 · 2021: 20 · 2020: 14 · 2019: 16 · 2018: 14 · 2017: 22 · 2016: 11 · 2015: 11 · 2014: 9 · 2013: 3
- FWCI
- 6.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health (AG00538, AG16573)
- U.S. Public Health Service (R01NSO20989)
- University of California, Irvine (P50 AG16573)
- National Institute on Aging (P01AG000538, R01AG020335, P50 AG 16573, AG 00538, P50AG016573, R01AG20335)
- National Institute of Neurological Disorders and Stroke
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K99AR054695)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Keywords
- lipoxin A4, Alzheimer's disease, neuroinflammation, amyloid-beta clearance, phagocytosis, NF-κB, inflammatory cytokines, IL-10, TGF-beta, Ym1, arginase-1, inducible nitric oxide synthase, synaptotoxicity, cognitive enhancement, anti-inflammatory lipid mediators
- MeSH terms
- Alzheimer Disease, Animals, Aspirin, Astrocytes, Brain, Cognition, Male, Mice, Inbred C57BL, Phenotype, Protein Processing, Post-Translational, Synapses, Amyloid beta-Peptides, NF-kappa B, Microglia, Neuroprotective Agents, Lipoxins, Mice
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