12/15-Lipoxygenase’s Role in AD Prevention
By Jessica Girdwain
“With the aging of baby boomers, we are about to be overwhelmed with Alzheimer’s patients,” says Samuel Gandy, MD, PhD, the Mount Sinai chair in Alzheimer’s disease research at the Mount Sinai School of Medicine in New York City. “By 2050, the entire budget of Medicare will be required just to care for Alzheimer’s.”
Such prospects make the discovery of potential treatments for combating this devastating terminal disease exciting. That’s why a new finding from researchers at the Temple University School of Medicine in Philadelphia is commanding the attention of the medical community. Researchers have uncovered the role a specific brain enzyme called 12/15-lipoxygenase (12/15 LO) plays in Alzheimer’s disease (AD). Three years ago, Domenico Praticò, MD, a professor of pharmacology at Temple, and his colleagues found that there was a marked increase in the protein in people with Alzheimer’s, but they didn’t understand its impact on the disease.
Their new findings, recently published in the Annals of Neurology, explain that 12/15 LO has a vital function: The protein regulates the enzyme beta secretase, which is involved in the development of amyloid plaques, a hallmark of AD. Researchers recognize this protein as the origin in a chain of events that leads to the disease’s progression.
“When we originally discovered the protein in the brain of AD patients, we immediately realized that it was elevated at the very early stages of the disease before the plaques develop. This observation opened up the intriguing possibility that the protein was one of the missing pieces of the puzzle,” Praticò says.
Researchers have found that an increase in the production of 12/15 LO is a way the body modulates the disease’s advancement. Overproduction of the protein triggers beta secretase, which produces more amyloid beta. “When the protein starts to work too much, it sends the wrong message that leads to a cascade of events that lead to Alzheimer’s,” Praticò says.
But he and his colleagues don’t yet know what triggers 12/15 LO to work too much. “That’s still a big mystery,” he notes, and it’s one that requires further study.
The discovery has important implications for future research, Gandy notes. “Inflammation has long been thought to play a role in Alzheimer’s, but clinical trials with NSAIDs have failed. Discovering the role of this enzyme gives us insight into the type of inflammation involved. Most importantly, the enzyme gives us a new drug target for controlling inflammation in Alzheimer’s.”
Earlier therapies attempted to look at controlling amyloid beta and gamma secretase to inhibit plaque accumulation in the brain, but both presented problems. Blocking gamma secretase can be toxic and can induce dangerous side effects in patients, making it a path that researchers can no longer follow. Beta secretase involves other concerns, including the fact that drugs that have been developed to control it cannot reach the brain and impact the disease. “We had been trying to reach the players in the disease but that failed. Now, we can go to the source—the 12/15 lipoxygenase—to stop the disease,” Praticò says.
The next step is to find out whether regulating this protein will control or prevent the disease, according to Praticò. To date, only animal models have been studied, but researchers hope to translate the discovery into a clinical application. “I hope in the next four to six months to have an answer to this question,” he says.
Praticò is currently testing a drug that blocks the enzyme as part of a prevention study that would indicate whether the drug could stop the disease before it starts. “Based on our preliminary data, we for sure know that we can prevent the disease. But the challenge with preventing a disease like Alzheimer’s is that if you treat it after it develops, it’s sometimes too late to make an impact.” That’s why it’s important to know whether the drug can reverse the disease, he says, which is something the researchers will examine next.
Looking to the future, if a preventive drug for AD is developed, who would likely receive it? Praticò points to the criteria currently on hand based on a large pool of scientific studies that indicate patients at high risk of AD. The most important aspect in identifying prospects to receive such treatment lies in recognizing mild cognitive impairment in people aged 55 to 65 who complain about being unable to remember information. “This isn’t just ‘Oh, where did I put my car key?’” Praticò notes. “These are people who can still function well and go to work but have an impaired ability to remember short-term information.”
Meeting the clinical definition of mild cognitive impairment doesn’t guarantee an individual will develop AD, but “40% to 50% of people in this risk group will develop Alzheimer’s,” Praticò says. It’s this group for whom physicians would prescribe the drug as a preventive measure.
Praticò is quick to point out that the research is far from complete. “This discovery can potentially be very exciting. It’s the first real mechanism in Alzheimer’s that we’ve discovered,” he says. “We didn’t discover the cure. There’s work to be done but the potential for what we found is enormous.”
— Jessica Girdwain is a Chicago-based freelance writer who has contributed health-related articles to several national magazines.