Research Paper|Volume 8, Issue 4|pp 664—684

Epigenetic mechanisms underlying cognitive impairment and Alzheimer disease hallmarks in 5XFAD mice

Christian Griñán-Ferré¹, Sara Sarroca³, Aleksandra Ivanova¹, Dolors Puigoriol-Illamola¹, Fernando Aguado², Antoni Camins¹, Coral Sanfeliu³, Mercè Pallàs¹

¹Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section) and Institute of Neuroscience, University of Barcelona, 08028 Barcelona, Spain
²Department of Cellular Biology, University of Barcelona, 08028 Barcelona, Spain
³Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, and IDIBAPS, 08036 Barcelona, Spain

Received: December 16, 2015Accepted: January 23, 2016Published: March 21, 2016

https://doi.org/10.18632/aging.100906

Copyright: © 2016 Griñán-Ferré et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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 and G9a. 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.