Age, but Not Amyloidosis, Induced Changes in Global Levels of Histone Modifications in Susceptible and Disease-Resistant Neurons in Alzheimer's Disease Model Mice.

Marcus Dyer,Andrew J Phipps,Phillippa C Taberlay,Adele Woodhouse,Stanislaw Mitew

doi:10.3389/fnagi.2019.00068

Abstract

There is increasing interest in the role of epigenetic alterations in Alzheimer’s disease (AD). The epigenome of every cell type is distinct, yet data regarding epigenetic change in specific cell types in aging and AD is limited. We investigated histone tail modifications in neuronal subtypes in wild-type and APP/PS1 mice at 3 (pre-pathology), 6 (pathology-onset) and 12 (pathology-rich) months of age. In neurofilament (NF)-positive pyramidal neurons (vulnerable to AD pathology), and in calretinin-labeled interneurons (resistant to AD pathology) there were no global alterations in histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 27 acetylation (H3K27ac) or histone 3 lysine 27 trimethylation (H3K27me3) in APP/PS1 compared to wild-type mice at any age. Interestingly, age-related changes in the presence of H3K27ac and H3K27me3 were detected in NF-labeled pyramidal neurons and calretinin-positive interneurons, respectively. These data suggest that the global levels of histone modifications change with age, whilst amyloid plaque deposition and its sequelae do not result in global alterations of H3K4me3, H3K27ac and H3K27me3 in NF-positive pyramidal neurons or calretinin-labeled interneurons.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of intracellular tau in neurofibrillary tangles and neuropil threads, and the deposition of insoluble extracellular β-amyloid (Aβ) plaques associated with dystrophic neurites and synapse loss (Braak and Braak, 1991; Thal et al, 2002)
No Alteration in the Percentage of Layer 2/3 NF-Labeled Pyramidal Neurons Co-localized With H3K4me3, H3K27me3 or H3K27ac in APP/PS1 Mice Compared to Age-Matched Wild-Type Mice
There was no alteration in the percentage of NF-positive pyramidal neurons co-localized with H3K27ac, H3K4me3 or H3K27me3 in APP/PS1 mice compared to wild-type mice at

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of intracellular tau in neurofibrillary tangles and neuropil threads, and the deposition of insoluble extracellular β-amyloid (Aβ) plaques associated with dystrophic neurites and synapse loss (Braak and Braak, 1991; Thal et al, 2002). A specific subset of excitatory pyramidal neurons that express neurofilament (NF) proteins are susceptible to neurofibrillary tangle formation, dystrophic neurite formation, synapse loss, degeneration and death in AD (Hof et al, 1990; Thangavel et al, 2009; Mitew et al, 2013a,b). There is increasing evidence that epigenetic alterations occur in the aging brain and AD (Gräff et al, 2012; Chouliaras et al, 2013; Lister et al, 2013; Ziller et al, 2013; Coppieters et al, 2014; De Jager et al, 2014; Lunnon et al, 2014; Benito et al, 2015; Gjoneska et al, 2015; Mastroeni et al, 2015; Gasparoni et al, 2018; Nativio et al, 2018), and that epigenetic changes occur early in AD and change in tandem with disease progression (De Jager et al, 2014; Lunnon et al, 2014; Sanchez-Mut et al, 2014; Gasparoni et al, 2018).

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