Posted October 7, 2022

Amyloid beta (Ab) is a key protein that forms into plaque bundles. It is cleaved from the larger amyloid precursor protein by gamma-secretase into shorter lengths (Ab37, Ab38) and longer lengths (Ab40, Ab42). The longer lengths of amyloid beta are more likely to clump together into toxic plaques.

Clinical trials more than a decade ago provided doses of a compound designed to completely inhibit the function of gamma-secretase. However, gamma-secretase has an important role in the brain, and blocking all of its natural and necessary activity resulted in significant negative side effects as well as an increase in cognitive decline.

With an increased understanding of the important role gamma-secretase has in the brain, CureAlz has funded studies to investigate the potential for a modulator of gamma-secretase (GSM). These novel agents alter the activity of gamma-secretase by selectively reducing levels of the longer, plaque-forming amyloid beta (Ab42) in favor of the shorter, nontoxic forms. In the lab, the GSM, at low and safe doses, decreased plaque formation and neuroinflammation. The next stage, Phase 1 clinical trials, has been supported by a $7 million grant from the National Institutes of Health.

A drug has been identified that alters the activity of gamma-secretase, an enzyme involved in the production of amyloid beta. The drug, classified as a gamma-secretase modulator (GSM), decreased amyloid plaque formation and inflammation, in animal models, usually associated with plaques in the brain.

The study was led by the late Steven Wagner, Ph.D., a member of the Cure Alzheimer’s Fund Research Leadership Group (RLG), and Rudy Tanzi, Ph.D., Chair of the CureAlz RLG. Also included as authors were CureAlz-funded scientist Gopal Thinakaran, Ph.D., and RLG member William Mobley, Ph.D., M.D. The results were published in the Journal of Experimental Medicine.

A hallmark of AD is the presence of amyloid plaques in the brain. Plaques are formed when amyloid beta proteins aggregate and stick together. Therefore, developing a drug that can interfere with the formation of plaques may prevent AD.

Amyloid beta is formed when beta- and gamma-secretase cleave amyloid precursor protein. Beta-secretase makes the initial cut, followed by gamma-secretase. Gamma-secretase can cut at multiple sites, resulting in different lengths of amyloid beta proteins. The longer lengths, especially Aβ42, are “sticky” and form plaques more readily than shorter forms. The genetic mutations responsible for early-onset AD often increase the longer forms of amyloid beta (Aβ40 and Aβ42). Because gamma-secretase can dictate which lengths of amyloid beta are formed, it has been a prime target for drug interventions.

Drugs that completely inhibit gamma-secretase activity have failed because gamma-secretase performs several essential functions in the brain and other organs. In a Rockefeller University Press article, Wagner explains that “GSMs, therefore, offer the ability to mitigate mechanism-based toxicities associated with gamma-secretase inhibitors.” The optimal drug intervention would alter, or modulate, the activity of gamma-secretase rather than inhibiting it entirely.

Over the years, the labs of Wagner and Tanzi have been working to develop effective and safe GSMs.  In this study, the researchers modified one of their previous GSMs to create a drug that showed no toxic side effects when tested in three different animal models. It also drastically decreased or eliminated the production of the longer forms of amyloid beta while increasing the shorter, less plaque-prone lengths.

When the drug was tested in a mouse model of early-onset Alzheimer’s disease, it showed similar results when administered either before or after substantial plaque formation. Plaque formation decreased, and so did plaque-associated inflammation. The results suggest that the drug may be successful even after plaques had formed. The low drug doses required for the beneficial effects were more than twenty-fold below the maximum tolerated dose.

Much like statins are taken to prevent coronary heart disease, a practical approach to treating AD would be a medication that could be started before or shortly after the onset of plaque formation. This study, presenting the full preclinical characterization of a new GSM, is the next step toward reaching that goal.

“In this study, we have pharmacologically characterized a potent GSM that, based on its preclinical attributes, appears to equal or exceed the potency of any previously tested GSMs,” explains Tanzi. “Future clinical trials will determine whether this promising GSM is safe in humans and could be used to effectively treat or prevent Alzheimer’s disease.”

The next phase, clinical trials, had been supported by a $7 million grant from the National Institutes of Health.

Steven Wagner, Ph.D., University of California, San Diego, Rudolph Tanzi, Ph.D., Massachusetts General Hospital, William Mobley, M.D., Ph.D., UC San Diego, Gopal Thinakaran, Ph.D., University of South Florida

Published in:

Journal of Experimental Medicine

Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention

Rockefeller University Press article: