New drug shows potential as prophylactic for 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 forming amyloid plaques. These plaques are pathological hallmarks of Alzheimer’s – clumps of misfolded proteins that accumulate in the brain, disrupting and killing neurons and resulting in the progressive cognitive impairment that is characteristic of the widespread neurological disorder.

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

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

According to the team, 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 Alzheimer’s.

Several attempts have been made to treat or prevent the condition 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.

The researchers investigated the therapeutic potential of drugs known as γ-secretase modulators (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 to cleave other protein targets.

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

The team created a novel GSM and tested it on mice, rats and macaques. They found that repeated, low doses of the GSM 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 percent.

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

The findings suggest that the novel GSM could be used prophylactically to prevent Alzheimer’s, either in patients with genetic mutations that increase their susceptibility 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 in humans and could be used to effectively treat or prevent Alzheimer’s disease,” said co-author Professor Rudolph Tanzi, at MGH.

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