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This study demonstrates that chronic DHA (docosahexaenoic acid) deficiency in neural tissue triggers a compensatory shift toward omega-6 fatty acids, which are more susceptible to oxidation and create damaging oxidized lipid products. The research identifies a protective mechanism where microglia initially clear these oxidized lipids from the neural retina, but prolonged accumulation causes microglial dysfunction and activates galectin-3, ultimately leading to neurodegeneration. Dietary DHA restoration reversed these pathological changes in mice, and similar omega-6 accumulation patterns were observed in naturally aged retinas.
Why it matters
These findings establish a mechanistic link between DHA deficiency and age-related neural decline, suggesting that dietary DHA supplementation could potentially prevent or reverse oxidative damage and inflammation in aging neural tissues. The identification of the galectin-3 pathway as a therapeutic target offers new intervention strategies for age-related neurodegenerative conditions.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: DHA deficiency drives neural oxidized-lipid stress and microglial activation