Northwestern University researchers have discovered that NU-9, an experimental drug already approved by the FDA for clinical trials in amyotrophic lateral sclerosis (ALS), shows significant promise for treating Alzheimer's disease. The small molecule compound demonstrated effectiveness in reducing toxic protein buildup in brain cells of animal models, suggesting a common mechanism connects these neurodegenerative conditions.
The study, published in March in the Proceedings of the National Academy of Sciences, revealed that NU-9 addresses the underlying mechanisms of disease rather than merely treating symptoms. This approach could potentially revolutionize treatment strategies for multiple neurodegenerative disorders.
"This drug is quite remarkable that it works in these multiple systems," said Richard B. Silverman, the inventor of NU-9 and Patrick G. Ryan/Aon Professor of Chemistry at Northwestern's Weinberg College of Arts and Sciences. "We need to test it in humans before we know how effective it is in treating Alzheimer's disease. But how well upper motor neurons function in mice is similar to how well they function in humans. So, it seems to me, NU-9 really should work."
Common Mechanisms in Different Neurodegenerative Diseases
The research team, co-led by William Klein, a professor of neurobiology at Weinberg and an expert on Alzheimer's disease, found that despite ALS and Alzheimer's involving different misfolded proteins, the underlying cellular damage mechanisms share similarities.
"What our study demonstrates is that the same mechanism affects two totally different proteins in two totally different diseases," explained Klein. "In both diseases, cells suffer from toxic protein buildup. It appears there is a common mechanism that gets rid of these proteins to prevent them from clustering. NU-9 is rescuing the pathway that saves the cell. It's very exciting."
In neurodegenerative diseases, misfolded proteins accumulate inside brain cells, causing toxicity that disrupts normal brain function and eventually leads to cell death. While ALS is associated with misfolded SOD1 proteins, Alzheimer's disease is characterized by misfolded amyloid beta oligomers.
"These are good proteins gone bad," Klein noted. "They are good proteins, but when they clump together, they play a role in their own build up. They stick to the cells, to the nearby cells and to the synapses. That causes brain dysfunction and, ultimately, brain cell death."
Promising Results in Laboratory and Animal Studies
The research team conducted experiments using both cellular cultures and mouse models. In cell cultures, they found that treating neurons with NU-9 before adding amyloid beta reduced protein buildup within cells and along dendrites. Remarkably, the protective effect persisted even after NU-9 was removed from the treated cells.
When administered orally to mice with Alzheimer's disease, NU-9 improved the animals' performance on memory tests. Follow-up studies also revealed that the drug reduced brain inflammation associated with Alzheimer's disease.
"Inflammation of the brain was prevented or greatly reduced by the treatment of NU-9," said Klein. "It stops the amyloid beta oligomer buildup, and stops the consequences of neuroinflammation, which causes a lot of damage in the brain. So, the drug is very powerful on two levels: cellular and whole animal."
Understanding NU-9's Mechanism of Action
While the exact mechanism of NU-9 remains under investigation, the researchers have made significant discoveries about how it works. They found that NU-9 specifically prevents the buildup of amyloid beta oligomers that form inside cells but doesn't affect protein formation outside cells.
Further analysis revealed that the drug's effectiveness relies on lysosomes, one of the cell's major recycling centers, and an enzyme called cathepsin B. In Alzheimer's disease, this recycling system is disrupted, causing amyloid beta to accumulate. NU-9 appears to help move amyloid beta proteins into the lysosomes, where cathepsin B then breaks down the protein clumps.
"Cells have two important 'junk compartments': the lysosome and the proteasome," Silverman explained. "They collect junk and other components that are not useful to the cell, chew them up and get rid of them. We found the proteasome wasn't involved at all. It's the lysosome that plays a role in how NU-9 works. But we're still trying to figure out exactly what NU-9 binds to in order to trigger the lysosome."
Klein added: "It's a black box phenomenon. It's like a relay race for moving these toxic clustered proteins around the cell. The proteins are clustered in one vesicle and then another vesicle and then finally handed off to the lysosome. We think NU-9 targets something in the early stage of that relay, but we don't know exactly what the target is."
Implications for Future Treatments
Silverman, who previously invented pregabalin (Lyrica) to treat fibromyalgia, nerve pain, and epilepsy, has founded Akava Therapeutics to commercialize NU-9. Meanwhile, Klein is a cofounder of Acumen Pharmaceuticals, which has a therapeutic monoclonal antibody for Alzheimer's disease currently in clinical trials.
The researchers plan to explore NU-9's effectiveness in other neurodegenerative diseases, including Parkinson's disease and Huntington's disease. They are also working to refine the compound to enhance its efficacy.
"It has long been thought that every neurodegenerative disease is a completely separate disease, but our findings suggest that common mechanisms might connect them," Silverman said. "This discovery opens the door to a new family of therapeutic compounds that, like NU-9, could control multiple degenerative diseases at a point before major damage to cells begins."
While the results are promising, the researchers emphasize that more rigorous testing is needed before human trials for Alzheimer's disease can begin. The study was supported by the National Institutes of Health and the Chemistry of Life Processes Institute.
