IN a new study published Tuesday in the Journal of Experimental Medicine (JEM), researchers at University of California San Diego School of Medicine, Massachusetts General Hospital and elsewhere have identified a new drug that could prevent Alzheimer’s disease (AD) by modulating, rather than inhibiting, a key enzyme involved in forming amyloid plaques.

In studies using rodents and monkeys, the researchers report the drug was found to be safe and effective, paving the way for possible clinical trials in humans.

“Alzheimer’s disease is an extraordinarily complex and multi-faceted condition that has, so far, defied effective treatment, let alone prevention,” said senior author Steven L. Wagner, professor in the Department of Neurosciences at UC San Diego School of Medicine. “Our findings suggest a potential therapy that might prevent one of the key elements of AD.”

Amyloid plaques are composed of small protein fragments called amyloid beta (Aβ) peptides. These peptides are generated by enzymes called β-secretase and γ-secretase, which sequentially cleave a protein called amyloid precursor protein on the surfaces of neurons to release Aβ fragments of varying lengths. Some of these fragments, such as Aβ42, are particularly prone to forming plaques, and their production is elevated in patients with mutations predisposing them to early-onset AD.

Several attempts have been made to treat or prevent AD using drugs that inhibit either β-secretase or γ-secretase, but many of these drugs have proved to be highly toxic or unsafe in humans, likely because β-secretase and γ-secretase are required to cleave additional proteins in the brain and other organs. Instead, Wagner and colleagues investigated the therapeutic potential of drugs known as γ-secretase modulators or GSMs, which instead of inhibiting the γ-secretase enzyme, slightly alter its activity so that it produces fewer Aβ peptides that are prone to form plaques while continuing in duties cleaving other protein targets.

“GSMs offer the ability to mitigate mechanism-based toxicities associated with γ-secretase inhibitors,” said Wagner. Researchers created a novel GSM, which in low doses eliminated Aβ42 production in mice and rats, without causing any toxic side effects. The drug was also safe and effective in macaques.(SD-Agencies)