New drug could prevent Alzheimer’s by altering a key enzyme involved in amyloid plaque formation

Amyloid plaques are pathology markers of Alzheimer’s disease (AD) – lumps of undigested proteins that accumulate in the brain, irritate and kill neurons and lead to progressive weakening of consciousness typical of the brain -broad brain order.

In a new study, published March 2, 2021 in the Journal of Experimental Medicine (JEM), researchers at the University of California San Diego School of Medicine, Massachusetts General Hospital and elsewhere have identified a new drug that can prevent AD by altering, rather than inhibiting, a key enzyme involved in the formation of amyloid plaques.

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

Alzheimer’s disease is a highly complex and multifaceted condition that has, to date, addressed effective treatment, not to mention prevention. Our findings suggest a treatment that may prevent one of the key elements of AD. “

Steven L. Wagner, PhD, Lead Author, Professor, Department of Neurosciences, UC San Diego School of Medicine

Amyloid plaques are made up of small pieces of a protein called amyloid beta (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 pest formation, and their production has increased in patients with predisposing mutations to early AD.

There have been several attempts to treat AD or prevent the use of drugs that inhibit either β-secretase or γ-secretase, but many of these drugs have been highly toxic or dangerous in humans, possibly due to the need for β-secretase and γ-secretase. to secrete excess proteins in the brain and other organs.

Instead, Wagner and colleagues studied the therapeutic potential of drugs called γ-secretase modulators or GSMs, which instead of inhibiting the γ-secretase enzyme, alter its activity so that it produce fewer Aβ peptides that tend to form blankets while continuing to clear other protein targets.

“GSMs offer the ability to mitigate equipment-based toxins associated with γ-secretase inhibitors,” Wagner said.

In the new JEM study, researchers created a novel GSM and tested mice, rats, and macaques. They found that low, low doses of GSM inhibited the production of Aβ42 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 percent.

The novel GSM was then tested in a mouse model of early AD, treating the animals either before or shortly after they began to create 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.

The findings suggest that the novel GSM may be used prophylactically to prevent AD, the authors wrote, both in patients with genetic mutations that increase vulnerability. to AD or in cases where amyloid plaques have been detected by brain scans.

“In this study, we have identified a medically robust GSM that, based on its preclinical properties, appears to equal or exceed any previously proven GSM capability,” he said. co-author Rudolph Tanzi, PhD, professor of neurology at Harvard Medical School and director of the Genetics and Aging Research Unit at Massachusetts General 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.”

Approximately 5 million Americans live with AD. The number of people with AD doubles every five years over the age of 65, according to the Centers for Disease Control, with the total number of Americans with the disease nearly tripling to 14 million by 2060. Currently, there is no known cure, only symbolic remedies.