New drug shows prophylactic potential against Alzheimer’s disease

Researchers have identified a new drug that could prevent Alzheimer’s disease by modulating, rather than inhibiting, a key enzyme involved in the formation of amyloid plaques. These plaques are pathological features of Alzheimer’s disease – clumps of misfolded proteins that build up in the brain, disrupting and killing neurons and leading to the progressive cognitive impairment characteristic of the common neurological disorder.

The study was conducted at the University of California (UC) San Diego School of Medicine and Massachusetts General Hospital (MGH), both in the United States.

“Alzheimer’s disease is an extraordinarily complex and multifaceted disease which, until now, has challenged effective treatment, let alone prevention,” said lead author Professor Steven Wagner of the faculty. of Medicine at UC San Diego. “Our results suggest a potential therapy that could prevent one of the key elements of Alzheimer’s disease.”

According to the team, amyloid plaques are made up 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 surface of neurons to release Aβ fragments of different lengths. Some of these fragments, such as Aβ42, are particularly prone to plaque formation and their production is high in patients with mutations predisposing them to early-onset Alzheimer’s disease.

Several attempts have been made to treat or prevent the disease using drugs that inhibit β-secretase or γ-secretase, but many of these drugs have been shown to be highly toxic or dangerous in humans, possibly because β- secretase and γ-secretase are needed to cleave additional proteins in the brain and other organs.

Researchers investigated the therapeutic potential of drugs known as γ-secretase modulators (GSM), which instead of inhibiting the enzyme γ-secretase, slightly alter its activity so that it produces fewer peptides. Aβ which are likely to form plaques while continuing to cleave other protein targets.

“GSM offers the ability to alleviate the mechanism-based toxicities associated with γ-secretase inhibitors,” said Wagner.

The team created a new mobile phone and tested it on mice, rats and macaques. They found that repeated low doses of GSM suppressed Aβ42 production in mice and rats, without causing toxic side effects. The drug was also safe and effective in macaques, reducing Aβ42 levels by up to 70 percent.

The new GSM was then tested in a mouse model of early-onset Alzheimer’s disease, treating the animals before or shortly after they started forming amyloid plaques. In both cases, the new GSM decreased the formation of plaques and reduced the inflammation associated with the plaque, which is believed to contribute to the development of the disease.

The results suggest that the new GSM could be used prophylactically to prevent Alzheimer’s disease, either in patients with genetic mutations that increase their sensitivity or in cases where amyloid plaques have been detected by brain scans, say the researchers.

“Future clinical trials will determine whether this promising GSM is safe for humans and could be used to effectively treat or prevent Alzheimer’s disease,” co-author Professor Rudolph Tanzi told the MGH.

The study was published in the Journal of Experimental Medicine (JEM).