Posted October 7, 2022

The buildup of amyloid beta in the brain is facilitated by gamma-secretase. In the lab, a gamma-secretase modulator has been effective in reducing plaque buildup, resulting in improved cognition. However, little is known about the regional expression or distribution of gamma-secretase in the brain. A positron emission tomography (PET) tracer has been developed to visualize gamma-secretase for the first time in animal models. This tracer will lead to a better understanding of AD and also support the continuing development of drugs with more accurate targeting of gamma-secretase.

Amyloid beta begins as the longer amyloid precursor protein (APP).  Two enzymes cut APP into the smaller amyloid beta form. The first cut is made by beta-secretase, followed by a second cut by gamma-secretase. Gamma-secretase can cut at different sites and produce amyloid beta with different lengths. Some lengths, particularly the amyloid beta with 42 amino acids, are toxic because they are “sticky” and clump together into plaques. Having a comprehensive understanding of gamma-secretase may provide researchers with insights leading to applications for targeted AD interventions. Essential to this understanding is knowing where gamma-secretase is expressed and distributed in the brain.

A PET scan is a non-invasive imaging technique that allows for the visualization of tissues or organs that are typically inaccessible, such as the brain. A small amount of radioactive material is attached to a tracer, which makes the tracer visible on scans.

A study by Rudy Tanzi, Ph.D., Chair of Cure Alzheimer’s Research Leadership Group, and the late Steven Wagner, Ph.D., a Cure Alzheimer’s Fund Research Leadership Group member, detailed a tracer to visualize gamma-secretase in the brain. The results were published in the Journal of Experimental Medicine.

Previously, the study’s researchers had developed a gamma-secretase modulator (GSM) that could bind to gamma-secretase and alter its activity to produce more of the nontoxic forms of amyloid beta. By radioactively labeling the GSM, an imaging agent was created that could be used to visualize where gamma-secretase was in the brain.

The GSM-based imaging agent was tested in various animal models, including models of AD. It was selective and only labeled gamma-secretase, and it could be used to measure the amount of gamma-secretase present. It also showed promise as being easily translated for human use.

This tracer will be a useful non-invasive tool that can be combined with other tracers or procedures to better define AD pathology. It may also help accelerate the search for therapies to cure AD.

Steven Wagner, Ph.D., University of California, San Diego, Rudolph Tanzi, Ph.D., Massachusetts General Hospital

Published in:

Journal of Experimental Medicine:

Molecular Imaging of Alzheimer’s Disease–Related Gamma-Secretase in Mice and Nonhuman Primates