Eicosanoid lipidome activation in post-mortem brain tissues of individuals with APOE4 and Alzheimer’s dementia
Open accessAbstract
Background: Chronic neuroinflammation is one of the hallmarks of late-onset Alzheimer’s disease (AD) dementia pathogenesis. Carrying the apolipoprotein ε4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, aberrant eicosanoid activation plays a prominent role in neurodegeneration. Methods: Using brains from the Religious Order Study (ROS), this study compared measures of brain eicosanoid lipidome in older persons with AD dementia to age-matched controls with no cognitive impairment (NCI), stratified by APOE genotype. Results: Lipidomic analysis of the dorsolateral prefrontal cortex demonstrated lower levels of omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and DHA-derived neuroprotectin D1 (NPD-1) in persons with AD dementia, all of which associated with lower measures of cognitive function. A significant interaction was observed between carrying the APOE4 allele and higher levels of both pro-inflammatory lipids and pro-resolving eicosanoid lipids on measures of cognitive performance and on neuritic plaque burden. Furthermore, analysis of lipid metabolism pathways implicated activation of calcium-dependent phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX), and soluble epoxide hydrolase (sEH) enzymes. Conclusion: These findings implicate activation of the eicosanoid lipidome in the chronic unresolved state of inflammation in AD dementia, which is increased in carriers of the APOE4 allele, and identify potential therapeutic targets for resolving this chronic inflammatory state.
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Numerous studies have identified abnormality of inflammation resolution in AD, including abnormality in the profile of SPMs and its receptors.
“Numerous studies have identified abnormality of inflammation resolution in AD, including the abnormality in the profile of SPMs and its receptors.175,425,426”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [175]
The Results and Discussion report altered SPM levels and describe chronic unresolved inflammation in AD dementia brain tissue. The Discussion proposes that lower sensitivity or expression of SPM receptors such as ALXR and GPR32 may explain some findings, but does not establish a receptor abnormality. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHigher dietary intake of omega-3 fatty acids is associated with reduced risk of dementia and cognitive decline, while pro-inflammatory omega-6 metabolites are positively correlated with Alzheimer's disease pathologies.
“Conversely, the pro-inflammatory metabolites of omega-6 fatty acids are positively correlated with AD pathologies (Fig. 3e).438 Indeed, a higher dietary intake of omega-3 fatty acids is associated with a reduced risk of dementia and cognitive decline.439”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [438]
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References 42 · Cited by 56
- Authors
- Ebright, B., Assante, I., Poblete, R. A., Wang, S., Duro, M. V., Bennett, D. A., Arvanitakis, Z., Louie, S. G., & Yassine, H. N.
- Affiliations
- University of Southern California (US)
- Rush University Medical Center (US)
- Corresponding author
- Louie, Stan G.
- Yassine, Hussein N.
- ORCID
- Venue
- Alzheimer's Research & Therapy
- Published
- 2022-10-11
- Volume
- 14
- Issue
- 1
- Pages
- 152-152
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC9552454
- OpenAlex
- W4304136250
- Cited by
- 56
- References
- 42
- Citations by year
- 2026: 16 · 2025: 10 · 2024: 15 · 2023: 13 · 2022: 2
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (P30AG10161, R01AG055770)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, APOE ε4, neuroinflammation, neuroprotection, omega-3 fatty acids, neuroprotectin D1, dorsolateral prefrontal cortex, cognitive function, neuritic plaques, phospholipase A2, 5-lipoxygenase, soluble epoxide hydrolase
- MeSH terms
- Lipidomics, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Arachidonate 5-Lipoxygenase, Brain, Calcium, Epoxide Hydrolases, Humans, Inflammation, Eicosapentaenoic Acid, Reactive Oxygen Species, Apolipoprotein E4, Phospholipases A2, Cytosolic
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