New class of drugs target brain metabolism to treat Alzheimer’s patients

Recent research highlights the potential of targeting the brain’s metabolism to treat Alzheimer’s disease, a condition that disrupts cognitive functions like memory and thinking.

Scientists from Stanford’s Knight Initiative for Brain Resilience, along with collaborators from institutions like the Salk Institute and Penn State University, have been investigating how to restore healthy brain function by focusing on the kynurenine pathway, a key regulator of brain metabolism.

The brain’s metabolism relies on glucose, the fuel that powers neurons, which are crucial for thought and memory. Alzheimer’s disease interferes with this process, causing a steady decline in cognitive abilities.

The scientists hypothesize that the kynurenine pathway becomes overactivated as amyloid plaque and tau proteins—both hallmarks of Alzheimer’s—build up in the brain. These proteins, believed to be key contributors to the disease, may trigger metabolic disruptions that harm the neurons' ability to communicate.

The breakthrough came when the research team discovered that blocking the kynurenine pathway in mice could improve cognitive function and memory. The scientists found that drugs targeting the kynurenine pathway helped restore the balance of the brain’s metabolism and improved behavior in mice engineered to develop Alzheimer’s-like symptoms.

Lead author Katrin Andreasson, a neurologist at Stanford University, explained, “We were surprised that these metabolic improvements were so effective at not just preserving healthy synapses but in actually rescuing behavior. The mice performed better in cognitive and memory tests when we gave them drugs that block the kynurenine pathway.”

The study, published in the journal Science, represents a collaboration across several top research institutions. The kynurenine pathway plays a crucial role in producing lactate, an energy molecule essential for neurons to function properly and maintain the connections, or synapses, that allow brain cells to communicate. Andreasson’s team focused on an enzyme called indoleamine-2,3-dioxygenase 1, or IDO1.

This enzyme generates kynurenine, and the researchers suspect that amyloid plaques and tau proteins overstimulate IDO1, leading to an overproduction of kynurenine. This disrupts the ability of astrocytes, the brain cells that support neurons, to supply lactate, which in turn affects brain metabolism and damages synapses.

Astrocytes, critical cells that normally support brain function, can’t produce sufficient lactate when the kynurenine pathway is overactive. Blocking the production of kynurenine in the laboratory experiments, however, restored the ability of astrocytes to provide energy to neurons, which helped stabilize brain function.

“The kynurenine pathway is overactivated in astrocytes, a critical cell type that metabolically supports neurons,” Andreasson noted. She added that when this pathway is disrupted, it results in damage to synapses and hampers cognitive abilities, a key issue in Alzheimer’s patients.

What makes these findings particularly promising is that drugs targeting the kynurenine pathway, specifically IDO1 inhibitors, are already in development for cancer treatments. These drugs, originally designed for oncology, can now potentially be repurposed for treating Alzheimer’s.

This offers a significant advantage in speeding up the process of testing these therapies in humans. “Best of all,” said Andreasson, “IDO1 is well known in oncology, and there are already drugs in clinical trials to suppress IDO1 activity and production of kynurenine.”

This ability to skip the lengthy process of developing new drugs from scratch could accelerate the time it takes to bring an effective Alzheimer’s treatment to market.

Andreasson’s team began testing the drugs in mice almost immediately, where they found that the intervention improved glucose metabolism in the hippocampus—a region critical for memory—and enhanced the performance of astrocytes. The mice were able to better navigate obstacle courses designed to assess spatial memory and cognition after receiving the IDO1-blocking drugs.

One of the most exciting aspects of this research is that these improvements in cognitive function were observed in mice that modeled both amyloid and tau protein pathologies, which are the two primary features of Alzheimer’s disease. “We also can’t overlook the fact that we saw this improvement in brain plasticity in mice with both amyloid and tau models. These are completely different pathologies, and the drugs appear to work for both,” Andreasson emphasized.

Looking ahead, there is great optimism that IDO1 inhibitors could be tested in human clinical trials for Alzheimer’s disease, with hopes of replicating the same cognitive improvements seen in lab animals. While earlier trials with these inhibitors focused on cancer outcomes, they did not track improvements in cognition or memory. Now, the research team is eager to apply these findings to Alzheimer’s patients.

Andreasson and her colleagues hope to initiate human trials to evaluate whether the same benefits can be observed in people with Alzheimer’s disease. If successful, this could be a game changer in Alzheimer’s treatment, leveraging existing drugs and therapies from the cancer field to help combat one of the most challenging neurodegenerative disorders.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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