Heneicosapentaenoic acid is produced from 2‐hydroxy‐docosahexaenoic acid via α‐oxidation: Implications for Alzheimer’s disease therapy

Abstract

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.