ArticleJournal of neuroinflammation2026
FADS1 contributes to anesthesia/surgery-induced cognitive impairment by aggravating omega-6 fatty acid metabolic disruption in aged mice.
Article in Journal of neuroinflammation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundPerioperative neurocognitive disorder (PND) is one of the most prevalent neurological complications in elderly surgical patients. Dysregulated lipid metabolism is a hallmark of aging and is strongly associated with cognitive dysfunction. This study aimed to investigate whether ω-6 polyunsaturated fatty acid (PUFA) metabolism contribute to PND and examined whether fatty acid desaturase 1 (FADS1) represents a key regulatory link between fatty acid metabolism and PND in aged mice.
methodsAn anesthesia/surgery-induced cognitive dysfunction model was established via laparotomy in 18-month-old C57BL/6J mice under 1.4% isoflurane anesthesia. Non-targeted metabolomics was performed in both mouse hippocampal tissue and human serum from post-operative cognitive dysfunction (POCD) patients to identify altered metabolic pathways. FADS1 expression was evaluated by western blotting and qPCR, and bilaterally hippocampal injection of recombinant AAV-shFads1 was used for gene knockdown. Behavioral outcomes were assessed using open field, Barnes maze, Y-maze, and fear conditioning tests. Western blotting, ELISA, and immunofluorescence were applied to evaluate downstream metabolic pathways, inflammatory cytokines, glial activation, and synaptic plasticity. Neuronal activity was assessed by sparse labeling, in vivo calcium fiber photometry, and in vivo electrophysiology. In addition, dietary docosahexaenoic acid (DHA) supplementation was administered to evaluate its effect on lipid metabolism, neuroinflammation, and postoperative cognitive function.
resultsAnesthesia/surgery significantly upregulated hippocampal FADS1 expression (1.91-fold [0.37] vs. 1.00-fold [0.43]; p < 0.01), leading to dysregulation of ω-6 PUFA metabolism. Elevated FADS1 promoted arachidonic acid (AA) accumulation (p < 0.01) and its downstream conversion to prostaglandin D2 (PGD2; p < 0.001), activating the prostaglandin D Receptor 1 (DP1) signaling cascade. This cascade induced a cytokine storm, microglial and astrocytic activation, reduced pyramidal neuron activity, synaptic dysfunction, and cognitive impairment. Knockdown of FADS1 reversed these metabolic disturbances, suppressed inflammatory responses, and improved learning and memory, whereas pharmacological DP1 activation abolished these protective effects. Consistently, serum metabolomics in POCD patients revealed persistent dysregulation of AA metabolism, supporting clinical relevance of this pathway. Furthermore, preoperative DHA supplementation attenuated FADS1 upregulation reduced PGD2/DP1 signaling, and partially rescued postoperative cognitive deficits in aged mice.
conclusionsThese findings highlight anesthesia/surgery could disrupt ω-6 PUFA metabolism, notably activating the PGD2/DP1 pathway, which promotes postoperative neuroinflammation, synaptic vulnerability, and cognitive decline. FADS1 emerges as a pivotal regulator of this pathway, and therapeutic modulation of the FADS1–PGD2–DP1 axis may offer a promising strategy for mitigating PND in the aging brain.
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