On the epigenetic derangement of HAT/HDAC balance in Alzheimer's Disease

Background Researchers believe that there is not a single cause of Alzheimer's, but rather it develops over time as a result of multiple factors such as lifestyle, environment, and genetics. In addition to studying specific genes that increase risk, researchers would also investigate biological mechanisms by which genes can be modified or activated. DNA encodes the genetic information in a cell. Histones are proteins that control how DNA is packaged inside cells. In response to certain chemical signals, histones control the unwrapping and wrapping of certain portions of DNA containing genes; this process helps turn genes on and off. This is achieved by adding modifications to histones that help improve gene activity. This includes attachment of chemical groups (called 'acetyl') to histones—a process known as 'histone acetylation' and removal of acetyl from histones referred to as 'histone deacetylation'. Increase in histone acetylation could impact memory formation. Recent studies have shown dysfunction of the histone acetylation process could be associated with brain changes observed in Alzheimer's. Cells contain specialized proteins (called enzymes) that either add or remove acetyl groups. The actions of the acetyl-adding enzymes could be opposed by enzymes that remove acetyl groups. Dr. Elisa Calcagno believes that a two-pronged approach involving activation of acetyl-adding enzymes and blocking of acetyl-removing enzymes may be helpful to tackle brain changes observed in Alzheimer's. These enzymes could be activated by chemical compounds. A compound was developed in the laboratory of Dr. Calcagno's mentor. The researchers found that this compound could activate enzymes associated with the histone acetylation process that could impact memory. Preliminary work by Dr. Calcagno's team shows that this compound may be nontoxic and may impact memory in genetically engineered Alzheimer's-like mouse. Research Plan Building on their initial findings, Dr. Calcagno and her research team will study a combination of compounds that could activate acetyl-addition and block acetyl-removal in the brains of Alzheimer's-like mouse models. The researchers will study the impact of these compounds by studying the levels of acetylation and gene regulation. The researchers will also test whether the combination of the compounds may be able to impact nerve cell activity associated with memory formation as well as cognition in the Alzheimer's-like mouse models. Impact The study findings could provide insights into how the biology of gene regulation could impact memory and brain changes observed in Alzheimer's. If successful, the results could give rise to potential therapeutic targets to tackle Alzheimer's.