Epigenetic change ups dementia?

A specific epigenetic switch appears to cause age-related memory loss in mice, suggesting this dysregulation could eventually serve as a biomarker for dementia, according to this week's Science. linkurl:Andre Fischer;https://www.uni-goettingen.de/de/57944.html at the linkurl:European Neuroscience Institute in Goettingen, Germany;https://www.eni.gwdg.de/ and his team found that older and younger mice exhibited marked differences in one type of epigenetic change to a specific region of one histone,

Written byLauren Urban

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A specific epigenetic switch appears to cause age-related memory loss in mice, suggesting this dysregulation could eventually serve as a biomarker for dementia, according to this week's Science. linkurl:Andre Fischer;https://www.uni-goettingen.de/de/57944.html at the linkurl:European Neuroscience Institute in Goettingen, Germany;https://www.eni.gwdg.de/ and his team found that older and younger mice exhibited marked differences in one type of epigenetic change to a specific region of one histone, leading to a suite of differences in gene expression between the two groups.

Histone deacetylase,HDAC
Image: Wikimedia commons,
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More importantly, this epigenetic change also appeared to impair learning in the older mice. Indeed, when the scientists injected older mice with a compound that restored the epigenetic pattern to roughly that of younger mice, the older mice learned tasks more easily, and showed similar gene expression to younger mice. The findings "identified an important epigenetic 'switch' that regulates genome-environment interactions which are important for learning and memory," Fischer told The Scientist. "This work implicitly suggests that the [specific epigenetic change] may represent a plausible biomarker" for the aged brain of species other than mice, said linkurl:Brigita Urbanc,;https://www.physics.drexel.edu/directory/faculty/homepage.html/?name=Urbanc a biophysicist who studies neurodegeneration at Drexel University. However, "more studies need to be done to verify if that is the case, and if this discovery is applicable to the human brain as well." Previous research has suggested that changes in gene expression may be behind the aging process. Given that acetylation of histones remodels chromatin and helps control gene expression (and has recently been linked to the formation of long-term memories), Fischer and his team set out to investigate whether changes to acetylation might play a role in cognitive decline. The researchers subjected younger (3 months) and older (16 months) mice to a variety of learning tests, and then examined gene expression in the hippocampus, one of the first regions affected by dementia. Indeed, older mice did not perform as well during the learning tests, and showed marked differences in gene expression. Specifically, after learning, the younger mice exhibited an upregulation of acetylation in the lysine residue 12 of histone H4 (H4K12), while older mice did not. As a result, after learning, younger mice showed a suite of changes in gene expression, often in genes linked to learning -- something older mice did not experience. To test the hypothesis that this specific type of altered acetylation might be the cause of learning problems, they injected a drug that boosts acetylation (by inhibiting a histone deacetylase, or HDAC) and found that older mice experienced an upregulation of H4K12 acetylation after learning tasks -- and learned those tasks more easily. "My team and I are very motivated to understand the mechanisms that underlie cognitive dysfunction during aging and Alzheimer's disease," Fischer said in an email. Scientists (including Fischer) have already suggested that "elevating histone-acetylation via HDAC inhibitors could be a suitable therapeutic strategy to treat dementia," Fischer added, and "now we know the very specific modification that needs to be targeted." S. Peleg et al., " Altered histone acetylation is associated with age-dependent memory impairment in mice," Science:328:753-6, 2010.
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