DHA deficiency drives neural oxidized-lipid stress and microglial activation
- 1Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI, USA
Abstract
Despite the well-established importance of DHA in neural health, the mechanisms by which neural tissues respond to declining DHA availability and how this response contributes to aging remain poorly understood. Here, we show that chronic DHA deficiency triggers a neural-specific compensatory lipid-remodeling program with pathological consequences. DHA loss causes a neural-tissue-selective shift from DHA-containing phospholipids toward arachidonic and adrenic acid-containing omega-6 species, accompanied by an RPE-associated polyunsaturated fatty acid biosynthetic program. This remodeling expands the pool of oxidation-prone lipids, redirects lipid peroxidation toward omega-6-derived products, and increases oxidative damage. Dietary DHA restoration reversed lipid remodeling, oxidative stress, inflammation, and visual dysfunction, establishing DHA deficiency as a causal driver of these phenotypes in mice. We identified an APOE-dependent oxidized-lipid disposal pathway that transfers oxidized lipid cargo from the neural retina to subretinal microglia, limiting its retention within the neural retina and protecting against degeneration. However, with persistent lipid uptake, oxidized phospholipids accumulate in microglial lysosomes, with sustained galectin-3 activation. Galectin-3 deficiency preferentially protected against later-stage degeneration, indicating that prolonged lipid burden converts the initial clearance response into a pathogenic response. Physiologically aged retinas also showed a similar shift toward omega-6 lipid accumulation. These findings define an adaptive-to-maladaptive lipid-remodeling-microglia axis linking declining DHA availability to age-related neural dysfunction.
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BibTeX
@misc{hagimori2026deficiency,
title = {{DHA deficiency drives neural oxidized-lipid stress and microglial activation}},
author = {R. Hagimori and P. Gogoi and P. K. Shahi and R. Ueno and G. Barrett-Wilt and M. Landowski and K. Oikawa and M. Tytanic and R. S. Brush and J. Wei and M. S. Guerriero and G. J. McLellan and S. Ikeda and M.-P. Agbaga and B. R. Pattnaik and K.-i. Yamada and A. Ikeda},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.753588},
url = {https://www.biorxiv.org/content/10.64898/2026.09.22.753588v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - DHA deficiency drives neural oxidized-lipid stress and microglial activation
AU - R. Hagimori
AU - P. Gogoi
AU - P. K. Shahi
AU - R. Ueno
AU - G. Barrett-Wilt
AU - M. Landowski
AU - K. Oikawa
AU - M. Tytanic
AU - R. S. Brush
AU - J. Wei
AU - M. S. Guerriero
AU - G. J. McLellan
AU - S. Ikeda
AU - M.-P. Agbaga
AU - B. R. Pattnaik
AU - K.-i. Yamada
AU - A. Ikeda
PY - 2026
DA - 2026/09/22
PB - bioRxiv
DO - 10.64898/2026.09.22.753588
UR - https://www.biorxiv.org/content/10.64898/2026.09.22.753588v1
AB - Despite the well-established importance of DHA in neural health, the mechanisms by which neural tissues respond to declining DHA availability and how this response contributes to aging remain poorly understood. Here, we show that chronic DHA deficiency triggers a neural-specific compensatory lipid-remodeling program with pathological consequences. DHA loss causes a neural-tissue-selective shift from DHA-containing phospholipids toward arachidonic and adrenic acid-containing omega-6 species, accompanied by an RPE-associated polyunsaturated fatty acid biosynthetic program. This remodeling expands the pool of oxidation-prone lipids, redirects lipid peroxidation toward omega-6-derived products, and increases oxidative damage. Dietary DHA restoration reversed lipid remodeling, oxidative stress, inflammation, and visual dysfunction, establishing DHA deficiency as a causal driver of these phenotypes in mice. We identified an APOE-dependent oxidized-lipid disposal pathway that transfers oxidized lipid cargo from the neural retina to subretinal microglia, limiting its retention within the neural retina and protecting against degeneration. However, with persistent lipid uptake, oxidized phospholipids accumulate in microglial lysosomes, with sustained galectin-3 activation. Galectin-3 deficiency preferentially protected against later-stage degeneration, indicating that prolonged lipid burden converts the initial clearance response into a pathogenic response. Physiologically aged retinas also showed a similar shift toward omega-6 lipid accumulation. These findings define an adaptive-to-maladaptive lipid-remodeling-microglia axis linking declining DHA availability to age-related neural dysfunction.
ER -