Amyloid plaques are pathological hallmarks of Alzheimer’s disease (AD) – clusters of poorly folded proteins that accumulate in the brain, interrupting and killing neurons and resulting in the progressive cognitive impairment that is characteristic of generalized neurological disorder.
In a new study, published on March 2, 2021 in the Journal of Experimental Medicine (JEM), researchers at the San Diego School of Medicine at the University of California, Massachusetts General Hospital and elsewhere have identified a new drug that could prevent DA modulating, rather than inhibiting, a key enzyme involved in the formation of amyloid plaques.
In studies with rodents and monkeys, the researchers reported that 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 multifaceted condition that has so far challenged effective treatment, let alone prevention,” said senior author Steven L. Wagner, PhD, professor in the Department of Neuroscience at UC San Diego School of Medicine. “Our findings suggest a potential therapy that may prevent one of the key elements of AD.”
The amyloid plaques are composed of small fragments of proteins called beta-amyloid peptides (Aβ). 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 high in patients with mutations that predispose them to early-onset AD.
Several attempts have been made to treat or prevent AD using drugs that inhibit β-secretase or γ-secretase, but many of these drugs have proven to be highly toxic or unsafe in humans, probably because β-secretase and γ-secretase are needed to cleave proteins additional 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 their activity to produce less Aβ peptides that are likely to form plaques. while continuing to duty to cleave other protein targets.
“GSMs offer the ability to mitigate mechanism-based toxicities associated with γ-secretase inhibitors,” said Wagner.
In the new JEM study, the researchers created a new GSM and tested it on mice, rats and monkeys. They found that low and repeated doses of GSM eliminated the production of Aβ42 in mice and rats, without causing any toxic side effects. The drug was also safe and effective in monkeys, reducing Aβ42 levels by up to 70 percent.
The new GSM was then tested on an early-onset AD mouse model, treating the animals before or shortly after they started to form amyloid plaques. In both cases, the new GSM reduced plaque formation and reduced plaque-associated inflammation, which appears to contribute to the development of the disease.
The findings suggest that the new GSM can be used prophylactically to prevent AD, the authors write, either in patients with genetic mutations that increase susceptibility to AD or in cases where amyloid plaques have been detected by brain scans.
“In this study, we pharmacologically characterize a potent GSM that, based on its preclinical attributes, appears to match or exceed the potency of any previously tested GSMs,” said co-author Rudolph Tanzi, PhD, professor of neurology at Harvard Medical School and director of the Genetic and Aging Research Unit at Massachusetts General Hospital.
“Future clinical trials will determine whether this promising GSM is safe in humans and can be used to effectively treat or prevent Alzheimer’s disease.”
It is estimated that 5 million Americans live with AD. The number of people with AD doubles every five years after age 65, according to the Centers for Disease Control, with the total number of Americans with the disease projected to almost triple to 14 million by 2060. There is currently no cure only symptomatic therapies.