Distinct lipid mediator profiles in brain and liver tissues in Alzheimer's disease
- 1University of California, Davis
Abstract
INTRODUCTIONInflammation plays a central role in Alzheimers Disease (AD), with oxylipins, endocannabinoids, and polyunsaturated fatty acids (PUFAs) acting as potent modulators. Soluble epoxide hydrolase (sEH), an enzyme with proinflammatory products, is upregulated in the AD brain. Emerging evidence suggests that AD-related inflammation may reflect systemic metabolic changes, however, peripheral organs remain understudied. Because the liver has a pivotal role in lipid metabolism and bioactive lipid mediator homeostasis, we hypothesized that inflammatory lipid mediator changes in the AD brain may be reflected in, and potentially shaped by, hepatic lipid metabolism.
METHODSPaired postmortem brain and liver tissues from 16 cognitively normal and 63 AD donors with median postmortem intervals (PMI) of 3.08 hours were analyzed for free and esterified forms of oxylipins and endocannabinoids. ANCOVA models evaluated effects of AD diagnosis, sex, and AD-by-sex interactions, adjusting for analytical batch, age, body mass index, and PMI.
RESULTSAD-associated differences in lipid mediator profiles were observed in both brain and liver, with a broader pattern of differences in liver. Differences involved CYP/sEH-related metabolites and fatty acid ethanolamides, with several metabolites also showing AD-by-sex interactions. Sex-associated differences were also more pronounced in the liver than the brain.
DISCUSSIONThese results suggest AD-associated lipid dysregulation across both central and peripheral tissues. The prominent hepatic alterations highlight the liver as an important site of peripheral lipid mediator dysregulation in AD and suggest that hepatic metabolic changes may contribute to or reflect inflammatory lipid remodeling in the brain.
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BibTeX
@misc{zhou2026distinct,
title = {{Distinct lipid mediator profiles in brain and liver tissues in Alzheimer's disease}},
author = {S. Zhou and K. Borkowski and N. Liang and T. G. Beach and G. Serrano and K. Kim and J. W. Newman and I. Maezawa and L.-W. Jin},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.26363708},
url = {https://www.medrxiv.org/content/10.64898/2026.09.22.26363708v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Distinct lipid mediator profiles in brain and liver tissues in Alzheimer's disease
AU - S. Zhou
AU - K. Borkowski
AU - N. Liang
AU - T. G. Beach
AU - G. Serrano
AU - K. Kim
AU - J. W. Newman
AU - I. Maezawa
AU - L.-W. Jin
PY - 2026
DA - 2026/09/22
PB - medRxiv
DO - 10.64898/2026.09.22.26363708
UR - https://www.medrxiv.org/content/10.64898/2026.09.22.26363708v1
AB - INTRODUCTIONInflammation plays a central role in Alzheimers Disease (AD), with oxylipins, endocannabinoids, and polyunsaturated fatty acids (PUFAs) acting as potent modulators. Soluble epoxide hydrolase (sEH), an enzyme with proinflammatory products, is upregulated in the AD brain. Emerging evidence suggests that AD-related inflammation may reflect systemic metabolic changes, however, peripheral organs remain understudied. Because the liver has a pivotal role in lipid metabolism and bioactive lipid mediator homeostasis, we hypothesized that inflammatory lipid mediator changes in the AD brain may be reflected in, and potentially shaped by, hepatic lipid metabolism. METHODSPaired postmortem brain and liver tissues from 16 cognitively normal and 63 AD donors with median postmortem intervals (PMI) of 3.08 hours were analyzed for free and esterified forms of oxylipins and endocannabinoids. ANCOVA models evaluated effects of AD diagnosis, sex, and AD-by-sex interactions, adjusting for analytical batch, age, body mass index, and PMI. RESULTSAD-associated differences in lipid mediator profiles were observed in both brain and liver, with a broader pattern of differences in liver. Differences involved CYP/sEH-related metabolites and fatty acid ethanolamides, with several metabolites also showing AD-by-sex interactions. Sex-associated differences were also more pronounced in the liver than the brain. DISCUSSIONThese results suggest AD-associated lipid dysregulation across both central and peripheral tissues. The prominent hepatic alterations highlight the liver as an important site of peripheral lipid mediator dysregulation in AD and suggest that hepatic metabolic changes may contribute to or reflect inflammatory lipid remodeling in the brain.
ER -