The hydroxylated form of docosahexaenoic acid (DHA-H) modifies the brain lipid composition in a model of Alzheimer's disease, improving behavioral motor function and survival

Abstract

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.

2-Hydroxy-Docosahexaenoic Acid Is Converted Into Heneicosapentaenoic Acid via α-Oxidation: Implications for Alzheimer’s Disease Therapy

“…This hypothesis was based on a lipidomic analysis of the 5xFAD mouse brain following DHA-H administration (Torres et al, 2014). However, here it appears that DHA levels are not significantly modified in the brain of WT or 5xFAD mice following DHA-H administration under similar conditions (Fiol-Deroque et al, 2013;Torres et al, 2014;Mohaibes et al, 2017). Therefore, the enrichment of brain membranes in highly polyunsaturated PE species must be mediated by an increase in PUFAs other than DHA and probably those derived from the HPA.…”

“…Here, a membrane lipid therapy perspective has been adopted to assess an AD therapy, assuming that the main events triggering the pathophysiology of AD are related to alterations in membrane lipid composition and structure (Escribá et al, 2008. DHA-H, a hydroxylated derivative of DHA, is a drug under pre-clinical development which have widely demonstrated potential therapeutic effects in AD and PD (Fiol-Deroque et al, 2013;Torres et al, 2014Torres et al, , 2015Mohaibes et al, 2017;Hernando et al, 2019). Here, we demonstrate that: (i) DHA-H is metabolically converted into HPA via α-oxidation; (ii) hydroxylation of DHA at the α-carbon confers resistance to its incorporation into other lipids and promotes its accumulation as a free fatty acid in cell membranes; (iii) DHA-H and DHA accumulate distinctly in cells and they regulate cellular lipid composition; (iv) hydroxylation of DHA at the α-carbon hinders its drug incorporation into cultured cells; (v) mouse administration of DHA-H leads to an increase in plasma HPA levels over and above those of DHA-H; (vi) brain DHA levels are not significantly modified by DHA-H administration; (vii) only HPA, and not DHA-H, is detected in the DHA-H-treated mouse brain; and (viii) HPA brain levels are closely related to improved spatial memory in 5xFAD mice.…”

“…To investigate the role played by HPA in the therapeutic effect of DHA-H in vivo, we assessed the metabolism of DHA-H and the production of HPA in WT and 5xFAD mice. The latter an AD mouse model in which DHA-H has widely demonstrated neuroprotective effects (Fiol-Deroque et al, 2013;Torres et al, 2014;Mohaibes et al, 2017). Initially, the levels of DHA-H and HPA were assessed in the blood plasma of WT mice administered DHA-H over 15 days with a repeated dose of 200 mg/kg daily.…”

“…The radial arm maze (RAM) is a spatial learning and memory test that allows both working and reference memory to be assessed (Wirsching et al, 1984), reflecting both hippocampal and frontal activity (Hasselmo and Howard, 2005;Martin and Clark, 2007). This test was previously used to assess the effect of DHA-H on 5xFAD spatial behavior, demonstrating a clear therapeutic effect of DHA-H at a daily dose ranging from 20 to 200 mg/kg with no apparent toxic effects (Torres et al, 2015;Mohaibes et al, 2017). Here, we correlated the brain levels of HPA in WT and 5xFAD mice with their performance in the RAM, assessing the total errors, the RMEs and the WMEs (Figures 5A-C).…”

“…Results from cell and animal models support the potential of DHA-H to treat AD. Data from a transgenic model of AD (5xFAD) has shown that DHA-H prevents cognitive decline in animals that received early treatment (from 3 to 7 months of age) (Fiol-Deroque et al, 2013;Mohaibes et al, 2017). In this sense, this effect on cognitive capacity is accompanied by an increase in neuronal cell proliferation in the hippocampus, suggesting that this therapy is mediated, at least in part, by a recovery of neurogenesis to healthy control levels (Fiol-Deroque et al, 2013).…”