title: Epigenetic mechanisms underlying cognitive impairment and Alzheimer disease hallmarks in 5XFAD mice.
abstract: 5XFAD is an early-onset mouse transgenic model of Alzheimer disease (AD). Up to now there are no studies that focus on the epigenetic changes produced as a result of Aβ-42 accumulation and the possible involvement in the different expression of related AD-genes. Under several behavioral and cognition test, we found impairment in memory and psychoemotional changes in female 5XFAD mice in reference to wild type that worsens with age. Cognitive changes correlated with alterations on protein level analysis and gene expression of markers related with tau aberrant phosphorylation, amyloidogenic pathway (APP, BACE1), Oxidative Stress (iNOS, Aldh2) and inflammation (astrogliosis, TNF-α and IL-6); no changes were found in non-amyloidogenic pathway indicators such as ADAM10. Epigenetics changes as higher CpG methylation and transcriptional changes in DNA methyltransferases (DNMTs) family were found. Dnmt1 increases in younger 5XFAD and Dnmt3a and b high levels in the oldest transgenic mice. Similar pattern was found with histone methyltransferases such as Jarid1a andG9a. Histone deacetylase 2 (Hdac2) or Sirt6, both related with cognition and memory, presented a similar pattern. Taken together, these hallmarks presented by the 5XFAD model prompted its use in assessing different potential therapeutic interventions based on epigenetic targets after earlier amyloid deposition.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section) and Institute of Neuroscience, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Christian
authors.initials: C
authors.lastname: Griñán-Ferré
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, and IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Sarroca
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section) and Institute of Neuroscience, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Ivanova
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section) and Institute of Neuroscience, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Puigoriol-Illamola
authors.affiliation: Department of Cellular Biology, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Aguado
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section) and Institute of Neuroscience, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, and IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Coral
authors.initials: C
authors.lastname: Sanfeliu
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section) and Institute of Neuroscience, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Pallàs
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer disease; behavior; cognition; deacetylase; methyltransferase; neurodegeneration