Changes in Histone H3 Acetylation on Lysine 9 Accompany Aβ 1-40 Overexpression in an Alzheimer's Disease Yeast Model

Abstract

Alzheimer's Disease (AD), the most common type of dementia, is a neurodegenerative disease characterized by plaques of amyloid-beta (Aβ) peptides found in the cerebral cortex of the brain. The pathological mechanism by which Aβ aggregation leads to neurodegeneration remains unknown. Interestingly, genetic mutations do not explain most AD cases suggesting that other mechanisms are at play. Epigenetic mechanisms, such as histone post-translational modifications (PTMs), may provide insight into the development of AD. Here, we exploit a yeast Aβ overexpression model to map out the histone PTM landscape associated with AD. We find a modest decrease in the acetylation levels on lysine 9 of histone H3 in the context of Aβ 1-40 overexpression. This change is accompanied by a decrease in RNA levels. Our results support a potential role for H3K9ac in AD pathology and allude to the role of epigenetics in AD and other neurodegenerative diseases.

Figure 1. Aβ 1-40 overexpression in yeast is accompanied by changes in H3K9ac levels

(A) Strains overexpressing Aβ 1-40 display mild growth suppression. Serial dilution growth assays for strains overexpressing Aβ 1-40 or a vector control grown in glucose or galactose-supplemented selective solid media. Black triangles indicate the relative concentrations of cells in the corresponding spots. (B) Expression of Aβ 1-40 verified by Western blotting. (C) Histone PTM levels are mostly unaffected by Aβ 1-40 overexpression in yeast. The bubble size represents the degree of change in the relative abundance of a histone modification. A smaller bubble represents a decrease in the levels of the modification, while a larger bubble represents an increase. The color scale depicts p-values derived from statistical analysis of Western blotting experiments. Red indicates changes with a p-value below 0.05, while gray indicates a p-value above 0.05. p-values were calculated using a two-tailed t test with Welch’s modification. (D) Acetylation on lysine 9 of Histone H3 is modestly decreased in the context of Aβ 1-40 overexpression. Graph displays the mean fold change in modification levels for Aβ 1-40 compared to vector control. Representative immunoblot shows the levels of lysine acetylation in Aβ 1-40 overexpression. Error bars indicate +SD (n=3). (*) p < 0.05. (E) Total RNA levels are decreased in Aβ 1-40 compared to vector control. Graph displays the mean fold change in total RNA levels for Aβ 1-40. Error bars indicate +SD (n=3). (*) p < 0.05.