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2019 Alzheimer's Association Research Fellowship (AARF)

ACSS2 and the Metabolic-Epigenetic Axis in Alzheimer's Disease

How could a protein help activate genes related to learning and memory and their potential role in Alzheimer’s disease?

Gabor Egervari, M.D., Ph.D.
University of Pennsylvania
Philadelphia, PA - United States


Histones are proteins that control how DNA is packaged inside cells. In response to signals, histones control the unwrapping and wrapping of certain portions of DNA containing genes, which 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.”
Recent studies have shown dysfunction of the histone acetylation process could lead to brain changes related to Alzheimer’s disease.  One protein that promotes histone acetylation is ACSS2 (acetyl-CoA synthetase 2). ACSS2 protein is found on genes required for learning and memory and its activity is associated with increased activity of these genes.

Research Plan

Dr. Egervari’s team will determine whether problems with ACSS2 may decrease histone acetylation during Alzheimer’s disease, leading to problems in learning and memory. The researchers will study the location of ACSS2 in brain tissue from people who had Alzheimer’s disease, and young and old adults who died from other causes. Next, Dr. Egervari will use genetically-engineered Alzheimer’s-like mice to study how ACSS2 and histone acetylation alter the activity of genes related to learning and memory. Finally, Dr. Egervari will track disease progression in Alzheimer’s-like mice genetically engineered to lack ACSS2, or to have unusually high levels of ACSS2. Combining human and mouse studies will help the researchers understand a common molecular pattern that may underlie healthy histone acetylation and during Alzheimer’s disease. The researchers will also test therapeutic chemical compounds in the Alzheimer’s-like mice, to identify those that may most strongly promote the function of ACSS2.


If successful, the study results could shed light on the role of ACSS2 in regulating how genes related to learning and memory are turned on and off during Alzheimer’s disease. The results could also establish ACSS2 as a therapeutic target for Alzheimer’s disease.

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