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

Authors
  • Parets, Sebastià1, 2
  • Irigoyen, Ángel3
  • Ordinas, Margarita1
  • Cabot, Joan2
  • Miralles, Marc1, 2
  • Arbona, Laura1
  • Péter, Mária4
  • Balogh, Gábor4
  • Fernández-García, Paula1, 2
  • Busquets, Xavier1
  • Lladó, Victoria1, 2
  • Escribá, Pablo V.1, 2
  • Torres, Manuel1, 2
  • 1 Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca , (Spain)
  • 2 Department of Neurosciences and Neurology, Laminar Pharmaceuticals SL, Palma de Mallorca , (Spain)
  • 3 Instrumental Techniques Laboratory, DDUNAV-Drug Development Unit-University of Navarra, Pamplona , (Spain)
  • 4 Institute of Biochemistry, Biological Research Centre, Szeged , (Hungary)
Type
Published Article
Journal
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Publication Date
Mar 27, 2020
Volume
8
Identifiers
DOI: 10.3389/fcell.2020.00164
PMID: 32292781
PMCID: PMC7122748
Source
PubMed Central
Keywords
License
Unknown

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease with as yet no efficient therapies, the pathophysiology of which is still largely unclear. Many drugs and therapies have been designed and developed in the past decade to stop or slow down this neurodegenerative process, although none has successfully terminated a phase-III clinical trial in humans. Most therapies have been inspired by the amyloid cascade hypothesis, which has more recently come under question due to the almost complete failure of clinical trials of anti-amyloid/tau therapies to date. 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 been tested in a number of animal models and has shown efficacy against hallmarks of AD pathology. 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, reaching higher concentrations than those of DHA-H itself. 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 incorporation into cell lipids and accumulation as free fatty acid in cell membranes. Finally, DHA-H administration to mice elevated the brain HPA levels, which was directly and positively correlated with cognitive spatial scores in AD mice, apparently in the absence of DHA-H and without any significant change in brain DHA levels. Thus, 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.

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