Epigenetic Alterations in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD.

Keywords: Alzheimer’s disease; DNA methylation; epigenetics; histone acetylation; histone methylation; histone phosphorylation; neuroepigenetics.

FIGURE 1

Epigenetics in Alzheimer’s disease (AD). (A) Different levels of investigation in AD pathology. At the population level, several genetic and non-genetic factors contribute to the risk for developing the disease. At the level of the individual, several pathophysiological characteristics such as altered glucose metabolism are observed in the brain of cognitively impaired AD patients. Associated with these alterations are – at the tissue and cellular level – yet other pathological hallmarks such as the presence of amyloid plaques and neurofibrillary tangles. Finally, at the intracellular level, higher levels of reactive oxygen species (ROS) and DNA damage, together with dysregulated gene transcription, splicing alterations and aberrant protein dynamics are also believed to be implicated in the onset and development of the pathology. (B) Similarly, epigenetic alterations have been reported in AD at different levels. Bulk histone acetylation (ac), phosphorylation (ph), and methylation (me) changes as well as DNA methylation (5mC) and hydroxymethylation (5hmC) alterations have been reported in AD tissues by IHC and WB. Major tendencies for these changes (as observed by several studies) are indicated by thick arrows. Locus-specific alterations mainly causing a repression of neuroplasticity genes and an activation of inflammatory genes have also been observed by ChIP using antibodies against histone modifications. Greater resolution is also possible for DNA methylation analysis in which nucleotide-specific alterations can be detected by oxi- and BS-sequencing. BS, bisulfite sequencing; ChIP, chromatin immunoprecipitation; CpG, cytosine-guanine dinucleotide; IHC, immunohistochemistry; IP, immunoprecipitation; WB, western blotting.