2024 Alzheimer's Association Research Grant (AARG)

Identification of Functional Cis-regulatory Elements of APP

How is the parent protein of beta-amyloid regulated in the brain?

Jesse Cochran, Ph.D.
HudsonAlpha Institute for Biotechnology
Huntsville, AL - United States

Background

Amyloid precursor protein (APP) is the parent molecule of beta-amyloid that can accumulate to form protein plaques in the brain, one of the hallmark changes in Alzheimer’s. These protein plaques can affect a person’s cognition and may contribute to symptoms of Alzheimer’s. The APP gene is a piece of DNA that contains the instructions for making APP. Research by Dr. Nicholas Cochran and others is beginning to clarify how the APP gene is activated inside brain cells to make APP protein. One emerging mechanism involves cis-regulatory elements, which are short stretches of DNA located near to a gene that may help to turn genes “on” or “off.”

Research Plan

For their current study, Dr. Cochran and colleagues will investigate potential cis-regulatory elements located near to the APP gene, and determine if these elements influence APP gene levels inside nerve cells. The researchers will study DNA found inside a specialized type of stem cell called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the body, including nerve cells, and grown in laboratory dishes. 

The researchers will first analyze several large databases containing human DNA sequences. They will identify thousands of potential cis-regulatory elements based on typical characteristics and past studies of these elements in DNA from individuals with Alzheimer’s. The researchers will then use genetic engineering to introduce genetic variations into these elements inside iPSC-derived nerve cells. Then, they will measure APP levels inside the cells. This will help the research team  understand which cis-regulatory elements are most closely linked to APP production inside cells.

In a second part of the study, Dr. Cochran’s team will use advanced genetic techniques to specifically target the most promising cis-regulatory elements. The researchers will directly activate, or inhibit, these elements inside the nerve cells. They will again measure APP levels inside the cells. By identifying genetic approaches that reduce APP production, the researchers will be able to pinpoint exactly which cis-regulatory elements might represent the most promising therapeutic targets in Alzheimer’s.

Impact

A better understanding of how APP is regulated inside nerve cells could lead to new therapeutic strategies designed to limit its activity in Alzheimer’s. This study could identify several genetic mechanisms that might be leveraged to help reduce APP levels in the brain during Alzheimer’s. Reducing APP levels might delay, or slow the formation of beta-amyloid protein plaques that are a hallmark of Alzheimer’s and other brain diseases.