Alzheimer's disease (AD) is a neurodegenerative pathology with relevant unmet therapeutic needs. Both natural aging and AD have been associated with a significant decline in the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), and accordingly, administration of DHA has been proposed as a possible treatment for this pathology. However, recent clinical trials in mild-to-moderately affected patients have been inconclusive regarding the real efficacy of DHA in halting this disease. Here, we show that the novel hydroxyl-derivative of DHA (2-hydroxydocosahexaenoic acid - OHDHA) has a strong therapeutic potential to treat AD. We demonstrate that OHDHA administration increases DHA levels in the brain of a transgenic mouse model of AD (5xFAD), as well as those of phosphatidylethanolamine (PE) species that carry long polyunsaturated fatty acids (PUFAs). In 5xFAD mice, administration of OHDHA induced lipid modifications that were paralleled with a reduction in amyloid-β (Αβ) accumulation and full recovery of cognitive scores. OHDHA administration also reduced Aβ levels in cellular models of AD, in association with alterations in the subcellular distribution of secretases and reduced Aβ-induced tau protein phosphorylation as well. Furthermore, OHDHA enhanced the survival of neuron-like differentiated cells exposed to different insults, such as oligomeric Aβ and NMDA-mediated neurotoxicity. These results were supported by model membrane studies in which incorporation of OHDHA into lipid-raft-like vesicles was shown to reduce the binding affinity of oligomeric and fibrillar Aβ to membranes. Finally, the OHDHA concentrations used here did not produce relevant toxicity in zebrafish embryos in vivo. In conclusion, we demonstrate the pleitropic effects of OHDHA that might prove beneficial to treat AD, which suggests that an upstream event, probably the modulation of the membrane lipid composition and structure, influences cellular homeostasis reversing the neurodegenerative process. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

We have compared the effect of the commonly used ω-3 fatty acid, docosahexaenoic acid ethyl ester (DHA-EE), and of its 2-hydroxylated DHA form (DHA-H), on brain lipid composition, behavior and lifespan in a new human transgenic Drosophila melanogaster model of Alzheimer's disease (AD). The transgenic flies expressed human Aβ42 and tau, and the overexpression of these human transgenes in the CNS of these flies produced progressive defects in motor function (antigeotaxic behavior) while reducing the animal's lifespan. Here, we demonstrate that both DHA-EE and DHA-H increase the longer chain fatty acids (≥18C) species in the heads of the flies, although only DHA-H produced an unknown chromatographic peak that corresponded to a non-hydroxylated lipid. In addition, only treatment with DHA-H prevented the abnormal climbing behavior and enhanced the lifespan of these transgenic flies. These benefits of DHA-H were confirmed in the well characterized transgenic PS1/APP mouse model of familial AD (5xFAD mice), mice that develop defects in spatial learning and in memory, as well as behavioral deficits. Hence, it appears that the modulation of brain lipid composition by DHA-H could have remedial effects on AD associated neurodegeneration. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

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Background Alzheimer’s disease (AD) is a neurodegenerative disease with as yet no efficient therapies. Many drugs and therapies have been designed and developed against this neurodegenerative disease, although none has successfully terminated a phase‐III clinical trial in humans. To shift the perspective for the design of new AD therapies, membrane lipid therapy has been tested, which assumes that brain lipid alterations lie upstream in the pathophysiology of AD. A hydroxylated derivative of docosahexaenoic acid was used, 2‐hydroxy‐docosahexaenoic acid (DHA‐H), which has shown efficacy against hallmarks of AD pathology in a transgenic mouse model of AD (5xFAD). Method Lipid samples were obtained from cultured cells and blood plasma and brain from WT and 5xFAD mice. Both, cell cultures and animals were treated with DHA‐H and DHA under different conditions. Mice were subjected to the Radial Arm Maze test during the last month of treatment just before sacrifice. Fatty acid analysis was performed by GC‐FID and GC‐MS (Gas Chromatography‐Flame Ionization Detector and ‐Mass Spectrometry) and the lipidomic analysis carried out by ESI‐MS (Electrospray ionization‐Mass Spectrometry). Result Here, for the first time, DHA‐H is shown to undergo α‐oxidation to generate the heneicosapentaenoic acid (HPA, C21:5, n‐3) metabolite, an odd‐chain omega‐3 polyunsaturated fatty acid that accumulates in cell cultures, mouse blood plasma and brain tissue upon DHA‐H treatment. Interestingly, DHA‐H does not share metabolic routes with its natural analog DHA (C22:6, n‐3) but rather, DHA‐H and DHA accumulate distinctly, both having different effects on cell fatty acid composition. This is partly explained because DHA‐H α‐hydroxyl group provokes steric hindrance on fatty acid carbon 1, which in turn leads to diminished uptake by cultured cells and accumulation as free fatty acid in cell membranes. Finally, DHA‐H administration to mice elevated the brain HPA levels which in turn were directly and positively correlated with cognitive spatial scores in AD mice. This effect appeared in the apparent absence of DHA‐H and without any significant change DHA levels in brain. Conclusion The evidence presented in this work suggest that the metabolic conversion of DHA‐H into HPA could represent a key event in the therapeutic effects of DHA‐H against AD.