Epigenetics Links Ageing with Alzheimer Disease

RESEARCH HIGHLIGHTS

Nature Reviews Neurology | Published online 23 Mar 2018; doi:10.1038/nrneurol.2018.36

ALZHEIMER DISEASE “Our analysis points to a new model in which AD is not simply an advanced or exacerbated state of normal ageing, but dysregulation Epigenetics links ageing of normal ageing,” explains Nativio. “The really exciting finding is that nor with Alzheimer disease mal ageing might provide protection against AD, and this protective aspect Dysregulation of epigenetic modi H4 (H4K16ac), a modification that has the potential to be enhanced.” fications could underlie the link is known to have an important role The team now plans to look between ageing and Alzheimer in ageing. They used chromatin further into the protective role of disease (AD), new research shows. immunoprecipitation followed by H4K16ac and to explore the roles of The findings suggest that AD does DNA sequencing (ChIP–seq) to ana other epigenetic modifications. They not result from amplification of lyse the genome-wide distribution also hope to exploit the potential the normal ageing process and that of H4K16ac in tissue from patients of their findings to provide a novel epigenetic dysregulation could be a with AD, elderly people (mean age therapeutic approach that does not novel therapeutic target. 68 years) and young cognitively focus on AD pathology. Ageing is the strongest risk factor healthy people (mean age 52 years). “Detection of plaques and tangles for AD, but the reason for this link is Both ageing and AD were associ happens late in the AD pathology, not known. On the basis of previous ated with redistribution of H4K16ac when neuronal loss has already work that has shown epigenetic when compared with the distribution advanced, but epigenetic alterations factors to influence ageing in model in tissue from the young group. occur much earlier, so targeting these animals, senior author Shelley However, an overall increase in alterations could represent an effective Berger, postdoctoral researcher H4K16ac was seen in normal ageing, therapeutic strategy,” explains Nativio. Raffaella Nativio and their colleagues whereas an overall loss of H4K16ac “Indeed, epigenetic changes are a ter AD is not investigated whether epigenetics was seen in AD. Furthermore, a rific target given that they are carried simply an might be involved. “We hypothesized subset of H4K16ac changes in AD out by enzymes that can be inhibited advanced or that the chromatin structure, which were opposite to those that occur or enhanced — our work advances exacerbated affects nuclear organization and gene in normal ageing, suggesting that the the foundation for such therapies.” expression, may be involved in ageing normal changes protect against AD. Ian Fyfe state of normal of the human brain and perhaps Further analysis showed that many ORIGINAL ARTICLE Nativio, R. et al. ageing progression of AD,” says Berger. H4K16ac changes in AD were in the Dysregulation of the epigenetic landscape of The researchers focused on vicinity of genes that have previously normal aging in Alzheimer’s disease. Nat. Neurosci. https://doi.org/10.1038/s41593-018-0101-9 (2018) acetylation of lysine 16 on histone been associated with AD.