A modern drug to prevent Alzheimer’s disease that is found to be safe and effective in animals

Researchers at the University of California San Diego School of Medicine and Massachusetts General Hospital have identified a new drug that could prevent Alzheimer’s disease by altering, rather than inhibiting, a key enzyme involved in the formation of amyloid plaques in the brain. The study, which will be published March 2 in the Journal of Experimental Medicine (JEM), demonstrating that the drug is safe and effective in rodents and monkeys, paving the way for future clinical trials in humans.

A major pathological symptom of Alzheimer’s disease involves the formation of amyloid plaques made up of small pieces of protein called amyloid-β (Aβ) peptides. These peptides are generated by an enzyme called β-secretase and γ-secretase, which subsequently clears a protein called amyloid precursor protein on the surface of neurons to release Aβ particles of varying lengths. . Some of these fragments, such as Aβ42, are particularly prone to the formation of amyloid plaques, and their production has increased in patients with mutations that predispose to early Alzheimer’s disease.

Several attempts have been made to treat or prevent Alzheimer’s disease with the use of drugs that inhibit either β-secretase or γ-secretase. But many of these drugs have been dangerous in humans, perhaps because β-secretase and γ-secretase are needed to secrete excess proteins in the brain and other organs.

A better approach could involve the introduction of drugs called γ-secretase modulators (GSMs), which, instead of inhibiting the γ-secretase enzyme, alter its activity so that it produces fewer Aβ peptides that tend to form pests while continuing to clear each other protein targets.

“GSMs therefore offer the potential to reduce equipment-based poisoning associated with γ-secretase inhibitors,” says Steven L. Wagner, PhD, professor in the Department of Neurosciences at UC San Diego School of Medicine .

In the new study, Wagner and colleagues developed a novel GSM and tested mice, rats, and macaques. Repeated low doses of the drug completely eliminated Aβ42 production in mice and rats without causing any toxic side effects. The drug was also safe and effective in macaques, reducing Aβ42 levels by up to 70%.

The researchers then tested the drug in a mouse model of early-onset Alzheimer’s disease, treating the animals either before or shortly after they began to form amyloid plaques. In each case, the novel GSM reduced plaque formation and reduced plaque-associated inflammation, which is thought to contribute to the development of disease.

This suggests that the drug may be used prophylactically to prevent Alzheimer’s disease, either in patients with genetic mutations that increase susceptibility to the disease or in cases where detect brain scans.

“In this study, we have identified a medically robust GSM that, based on its preclinical properties, appears to equal or exceed the potential of any previously tested GSMs,” Dr. Rudolph E. Tanzi, Professor of Neurology at Harvard and Massachusetts General contributes to Hospital. “Future clinical trials will determine whether this promising GSM is safe in humans and whether it could be used to treat or prevent Alzheimer’s disease.”