2022 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

NHE6 Inhibition: A Novel Paradigm For Neutralizing ApoE4 Risk

How do gene variations impact Alzheimer’s risk, and how might those risks be mitigated?

Joachim Herz, M.D.
University of Texas Southwestern Medical Center
Dallas, TX - United States

Background

The apolipoprotein E (APOE) gene makes the ApoE protein, which is thought to help carry fats throughout the body. There are several APOE gene variations, including APOE-e2, APOE-e3 and APOE-e4. Possessing the APOE-e4 variation is thought to impact the risk of developing Alzheimer’s in some populations, but how it does so is not yet understood. 

A hallmark of Alzheimer’s is the clumping of beta-amyloid, a protein fragment, into sticky plaques within the brain. This clumping may occur, in part, because the brain loses its ability to clear beta-amyloid molecules effectively. However, scientists remain uncertain exactly how this clearance mechanism might be damaged in Alzheimer’s.

In previous research, Dr. Joachim Herz and colleagues found that APOE-e4 causes defects in how materials are moved in and out of cells. The research team showed that inhibiting or reducing a protein called sodium-hydrogen exchanger 6 (NHE6, a protein which is involved in the process of removing molecules in and out of cells) corrected these defects and reduced the accumulation of beta-amyloid.

Research Plan

In a series of experiments, Dr. Herz and colleagues will study the effectiveness, mechanism, and safety of inhibiting NHE6 to reduce the risk of Alzheimer’s associated with the APOE-e4 gene variation. First, they will treat genetically engineered Alzheimer’s-like mice with a drug known to inhibit proteins related to NHE6. They will determine if the drug can stimulate the removal of beta-amyloid particles from the brain. Next, to determine if inhibiting NHE6 will also impact beta-amyloid clearance, the researchers will treat genetically engineered Alzheimer’s-like mice with other potential drugs engineered to inhibit NHE6. Finally, if these results seem promising, Dr. Herz and colleagues will identify, validate, and establish new compounds that specifically inhibit NHE6.

Impact

In addition to better understanding of the biological underpinnings related to APOE, the results may identify NHE6 as a potential therapeutic target for treatment in Alzheimer’s, especially in those with the APOE-e4 gene variation.