title: Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates.
abstract: Amyloid-ß (Aß) fragments, oligomeric Aß aggregates, and pyroglutamylated-Aß peptides, as well as epigenetic mechanisms and autophagy dysfunction all appear to contribute in various ways to Alzheimer's disease progression. We previously showed that dietary supplementation of oleuropein aglycone, a natural phenol abundant in the extra virgin olive oil, can be protective by reducing Aß42 deposits in the brain of young and middle-aged TgCRND8 mice. Here, we extended our study to aged TgCRND8 mice showing increased pE3-Aß in the brain deposits. We report that oleuropein aglycone is active against glutaminylcyclase-catalyzed pE3-Aß generation reducing enzyme expression and interferes both with Aß42 and pE3-Aß aggregation. Moreover, the phenol astonishingly activates neuronal autophagy even in mice at advanced stage of pathology, where it increases histone 3 and 4 acetylation, which matches both a decrease of histone deacetylase 2 expression and a significant improvement of synaptic function. The occurrence of these functional, epigenetic, and histopathologic beneficial effects even at a late stage of the pathology suggests that the phenol could be beneficial at the therapeutic, in addition to the prevention, level.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Luccarini
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Grossi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rigacci
authors.affiliation: Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Coppi
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pugliese
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pantano
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy; Department of NEUROFARBA, Newborn Screening, Clinical Chemistry and Pharmacology Lab, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy; Department of NEUROFARBA, Newborn Screening, Clinical Chemistry and Pharmacology Lab, Meyer Children's University Hospital, Florence, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ed Dami
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Berti
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Stefani
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy. Electronic address: fiorella.casamenti@unifi.it.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Casamenti
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology* / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D003864:Depression, Chemical; D019587:Dietary Supplements; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D057888:Iridoid Glucosides; D039823:Iridoids / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D008822:Mice, Transgenic; D000069463:Olive Oil; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity*; D010938:Plant Oils / Q000737:chemistry; D066329:Protein Aggregates / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D006657:Histones; D057888:Iridoid Glucosides; D039823:Iridoids; D000069463:Olive Oil; D010446:Peptide Fragments; D010938:Plant Oils; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); C002769:oleuropein; D056464:Histone Deacetylase 2
keywords: Alzheimer's disease; Epigenetics; Glutaminyl cyclase; Long-term potentiation; Oleuropein aglycone; Pyroglutamylated-3 Aß; TgCRND8 mice