Drugs designed to help the immune system fight cancer might also stave off dementia, according to a study in mice. Researchers at Stanford University discovered a new role for the metabolic enzyme IDO1 in Alzheimer’s disease and found that blocking the enzyme with a cancer drug improved brain metabolism and memory in mice.
Donald WeaverThe new study, published last week in Science, is part of a growing effort to tease apart the metabolic and immune components of Alzheimer’s. Genomic and proteomic studies are increasingly pointing researchers beyond the boundaries of amyloid and tau, the two protein baddies that accumulate in Alzheimer’s patients, and that drugmakers have spent billions chasing.
“One thing that Alzheimer’s research needs are new thoughts and new ideas. And from a biology perspective, this paper delivers on that,” Donald Weaver, a chemist and neurologist at the University Health Network in Toronto who wasn’t involved in the study, told Endpoints News.
IDO1 inhibitors were once a hot class of experimental cancer drugs. The enzyme makes a molecule called kynurenine, which helps shut down immune responses. But tumor cells can hijack the process and produce more kynurenine to stop immune cells from attacking. Drugmakers hoped to that blocking IDO1 would help other immunotherapies do a better job, but the approach was unsuccessful in the clinic.
But the researchers found new functions for the enzyme and its metabolite in the brain. Having too much kynurenine shuts down glucose metabolism in the brain cells called astrocytes, and prevents them from feeding neurons the lactate molecules that they crave.
Katrin Andreasson“This shows that IDO1 is involved in even more processes than we realized and gives us even more enthusiasm to exploit this as an immune target,” Weaver said. By knocking out the gene for IDO1 or inhibiting the enzyme with an experimental Pfizer drug called PF068, they restored metabolism and memory impairments in mice.
“We were completely stunned by how protective it was. And we hadn’t expected anything like that,” said Katrin Andreasson, a neuroscientist at Stanford who led the research.
Pfizer wasn’t involved in the study, and it’s unclear if the company would be interested in testing the compound in Alzheimer’s, but Andreasson said she is already talking to her colleagues at Stanford about a potential clinical trial. “There’s a lot of interest, so I am hoping that it will get off the ground,” she said.
Changing brain metabolism
It’s well known among Alzheimer’s researchers that brain metabolism — especially glycolysis, the breakdown of glucose to create energy — changes early in the disease. PET scans that use a radioactive version of glucose show that a diminished brain metabolism begins a decade or more before the first signs of memory loss in Alzheimer’s.
Nick Seyfried“They’re really good biomarkers,” said Nick Seyfried, a biochemist and neurodegenerative disease researcher at Emory University School of Medicine. “And if you can monitor something that early in the disease course, could you then intervene earlier?”
Seyfried, who wasn’t involved in the IDO1 study, said he was unfamiliar with the enzyme’s role in Alzheimer’s but was encouraged by the new line of work. Other scientists told Endpoints that scientists have found elevated levels of IDO1 in the brains of patients who died of Alzheimer’s, and a few academic labs have studied the protein’s role in mouse models. But they said that Andreasson’s study added a new level of rigor.
“This is a very interesting and provocative finding,” Michael Platten, a neurologist at the German Cancer Research Center in Heidelberg, said in an email. Although kynurenine has been linked to neurotoxicity in the past, “this study very elegantly gives a detailed mechanistic insight.”
Michael PlattenWeaver noted that most drugs developed for cancer don’t cross the blood-brain barrier, and thus couldn’t be repurposed for testing in Alzheimer’s disease. The Pfizer compound gets into the brain, but Weaver’s lab has also created new IDO1 inhibitors with an emphasis on brain access.
Intriguingly, amyloid and tau seemed to spur the production of IDO1 in Andreasson’s mice, and blocking the enzyme staved off further amyloid and tau buildup. The results suggest that the altered metabolism is not merely a symptom of those protein aggregates but intertwined with the disease.
“That was really interesting,” Seyfried said. “You have a drug that can reduce tau and impact amyloid. That would fit into the rubric for moving a drug forward in clinical trials.”
“My only reservation is let’s see if it works in humans. We have seen a lot of studies like this where we’ve been able to impact amyloid and tau in preclinical models that have ultimately failed in the clinic,” Seyfried added. “The biggest question is when to treat humans. It may not have an impact if you treat too late, so we will need to think deeply about who to enroll.”