Epigenetic Mechanisms in Memory and Cognitive Decline Associated with Aging and Alzheimer's Disease

Abstract

Epigenetic mechanisms, which include DNA methylation, a variety of post-translational modifications of histone proteins (acetylation, phosphorylation, methylation, ubiquitination, sumoylation, serotonylation, dopaminylation), chromatin remodeling enzymes, and long non-coding RNAs, are robust regulators of activity-dependent changes in gene transcription. In the brain, many of these epigenetic modifications have been widely implicated in synaptic plasticity and memory formation. Dysregulation of epigenetic mechanisms has been reported in the aged brain and is associated with or contributes to memory decline across the lifespan. Furthermore, alterations in the epigenome have been reported in neurodegenerative disorders, including Alzheimer's disease. Here, we review the diverse types of epigenetic modifications and their role in activity- and learning-dependent synaptic plasticity. We then discuss how these mechanisms become dysregulated across the lifespan and contribute to memory loss with age and in Alzheimer's disease. Collectively, the evidence reviewed here strongly supports a role for diverse epigenetic mechanisms in memory formation, aging, and neurodegeneration in the brain.

Keywords: DNA; epigenetics; hippocampus; histone; memory; neurodegeneration.

Figure 1

Overview of epigenetic mechanisms. DNA is packaged into the chromosome as chromatin which is wrapped around the nucleosome structure containing two copies each of the core histone proteins (H2A, H2B, H3, and H4) with protruding N-terminal tails. (A) Several post-translational modifications (PTMs) can occur at histone proteins to regulate chromatin structure and gene transcription. Epigenetic PTMs of histones associated with a heterochromatin state (top) include methylation (black), ubiquitination (purple), sumoylation (aqua), and dopaminylation (orange). Specific histone modification sites associated with heterochromatin state for each group of PTMs are described as associated marks (red box). Epigenetic PTMs of histones associated with a euchromatin state (bottom) include methylation (black), phosphorylation (pink), acetylation (green), serotonylation (yellow), and ubiquitination (purple). Specific histone modification sites associated with euchromatin state for each group of PTMs are described as associated marks (blue box). (B) DNA methylation is an epigenetic mechanism that can be associated with either active or repressed transcription. The circle indicates a portion of DNA that is magnified within the black outlined box (right). The 5mC mark (black) is established on a cytosine residue and is associated with transcriptional repression. The TET enzymes (blue) are recruited to the 5mC mark to initiate the demethylation process. The 5mC mark (black) is converted to the 5hmC mark (orange), which is associated with active gene transcription. Nucleotides are illustrated as follows: Thymine (T; green), Adenine (A; orange), Guanine (G; pink), Cytosine (C; blue).

Figure 2

Epigenetic marks altered in the brain during Alzheimer’s disease (AD) compared to normal aging. This figure compares several epigenetic marks dysregulated in the brain of AD patients and rodent models with that of normal aging. The marks that change similarly in both conditions are in the circle and marks that change only in one condition are listed separately. The arrows show the direction of the marks’ changes.