title: Membrane lipid modifications and therapeutic effects mediated by hydroxydocosahexaenoic acid on Alzheimer's disease.
abstract: 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.
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain. Electronic address: manuel.torres.phd@gmail.com.
authors.forename: Manuel
authors.initials: M
authors.lastname: Torres
authors.affiliation: Division of Brain Sciences, Imperial College London, London, United Kingdom.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Price
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Fiol-Deroque
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Marcilla-Etxenike
authors.affiliation: Biophysics Unit (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country, Bilbao, Spain.
authors.forename: Hasna
authors.initials: H
authors.lastname: Ahyayauch
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Barceló-Coblijn
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Terés
authors.affiliation: Division of Brain Sciences, Imperial College London, London, United Kingdom.
authors.forename: Loukia
authors.initials: L
authors.lastname: Katsouri
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Ordinas
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: David J
authors.initials: DJ
authors.lastname: López
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: Maitane
authors.initials: M
authors.lastname: Ibarguren
authors.affiliation: Biophysics Unit (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country, Bilbao, Spain.
authors.forename: Félix M
authors.initials: FM
authors.lastname: Goñi
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Busquets
authors.affiliation: IBIS Seville Biomedical Research Institute, Virgen del Rocio University Hospital, CSIC - University of Seville, and CIBERNED, Seville, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Vitorica
authors.affiliation: Division of Brain Sciences, Imperial College London, London, United Kingdom. Electronic address: m.sastre@imperial.ac.uk.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sastre
authors.affiliation: Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain. Electronic address: pablo.escriba@uib.es.
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Escribá
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000502:physiology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013107:Sphingolipids / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D053835:Unilamellar Liposomes / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; C558298:Mapt protein, mouse; D008563:Membrane Lipids; C508853:PSEN1 protein, human; D010743:Phospholipids; D053764:Presenilin-1; D012333:RNA, Messenger; D013107:Sphingolipids; D053835:Unilamellar Liposomes; D016875:tau Proteins; D004281:Docosahexaenoic Acids; D002784:Cholesterol
keywords: Alzheimer's disease; Amyloid-β; DHA; Lipid; Lipid rafts; Membrane; Tau phosphorylation