Histone Modifications in Alzheimer's Disease

Abstract

Since Late-onset Alzheimer's disease (LOAD) derives from a combination of genetic variants and environmental factors, epigenetic modifications have been predicted to play a role in the etiopathology of LOAD. Along with DNA methylation, histone modifications have been proposed as the main epigenetic modifications that contribute to the pathologic mechanisms of LOAD; however, little is known about how these mechanisms contribute to the disease's onset or progression. In this review, we highlighted the main histone modifications and their functional role, including histone acetylation, histone methylation, and histone phosphorylation, as well as changes in such histone modifications that occur in the aging process and mainly in Alzheimer's disease (AD). Furthermore, we pointed out the main epigenetic drugs tested for AD treatment, such as those based on histone deacetylase (HDAC) inhibitors. Finally, we remarked on the perspectives around the use of such epigenetics drugs for treating AD.

Keywords: Alzheimer’s disease; aging; histone modifications.

Figure 1

The action of histone deacetylase inhibitors (HDACi) on histone acetylation and chromatin accessibility. HDACs promote the loss of histone acetylation by the removal of acetyl groups, which in turn causes a conformational change in the chromatin structure and, consequently, gene repression. In contrast, the use of HDACi prevents the action of HDACs, maintaining histone acetylation marks and activating gene expression.

Figure 2

Dysregulation of epigenetic modifications in AD. In the healthy brain, there are a number of epigenetic modifications thar occur on histone tails, such as acetylation, methylation, and phosphorylation (A). In AD brains, however, gains or losses of histone modifications can be observed (B).