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A recent study from Northwestern University has highlighted the potential of an experimental drug, NU-9, which has received FDA approval for clinical trials aimed at treating amyotrophic lateral sclerosis (ALS). This study reveals that NU-9 also enhances neuron health in animal models afflicted with Alzheimer’s disease.
Both ALS and Alzheimer’s are characterized by the presence of misfolded proteins that severely impact brain health. Unlike treatments that primarily target the specific symptoms of these diseases, NU-9 takes a more comprehensive approach by addressing the underlying disease mechanisms. Findings from this research suggest that NU-9 might be effective against core processes that contribute to various neurodegenerative disorders.
“The versatility of this drug across different neurological systems is quite remarkable,” stated Richard B. Silverman from Northwestern, the inventor of NU-9. “We must conduct human trials to ascertain its efficacy for Alzheimer’s, yet it appears promising based on how motor neurons operate in mice, which share similarities with human neural function.”
The study, which was published on March 3 in the Proceedings of the National Academy of Sciences, demonstrated the drug’s effectiveness through both cellular cultures and an initial study involving mice.
“Our research indicates a shared mechanism that impacts two distinct proteins in two different diseases,” explained William Klein, a co-corresponding author of the study. “Both conditions exhibit toxic protein accumulations within cells, and NU-9 appears to activate pathways that mitigate this toxic build-up, showcasing its potential to restore cell health.”
Silverman, who is also known for developing pregabalin (Lyrica) for conditions such as fibromyalgia and epilepsy, occupies the Patrick G. Ryan/Aon Chair of Chemistry at Northwestern’s Weinberg College of Arts and Sciences and is the founder of Akava Therapeutics, the company advancing NU-9. Klein, an expert in Alzheimer’s pathology, holds a professorship in neurobiology at Weinberg and co-founded Acumen Pharmaceuticals, which is developing a monoclonal antibody for Alzheimer’s treatment currently in clinical evaluation.
In neurodegenerative conditions, proteins that misfold accumulate within brain cells, leading to toxicity that disrupts normal functions and ultimately results in cell death. Specific proteins, such as misfolded SOD1 associated with ALS and amyloid beta oligomers linked to Alzheimer’s, play crucial roles in these processes.
“These proteins have beneficial roles under normal circumstances but become detrimental when they aggregate,” Klein noted. “Their clumping leads to dysfunction in neighboring cells and synapses, culminating in brain cell death.”
Previous investigations by Silverman and collaborator P. Hande Ozdinler, an associate professor of neurology, found that NU-9 aided cells in eliminating protein aggregates caused by unrelated mutated proteins, which restored neuron function in ALS models. This prompted further exploration into the drug’s potential impact on Alzheimer’s pathology.
To investigate this, the team used neuron cultures derived from a small animal model. In their experiments, they exposed neurons to amyloid beta, which resulted in rapid aggregation and adhesion to the cells. However, treatment with NU-9 beforehand resulted in drastically reduced protein accumulation within the neurons and along their dendrites. Remarkably, the protective benefits of NU-9 persisted even after the drug was removed.
Subsequently, the researchers progressed to whole animal trials, administering oral NU-9 to mice modelled with Alzheimer’s disease, which revealed improvements in memory test performance. Follow-up studies unveiled that NU-9 also diminished brain inflammation linked to Alzheimer’s.
“The neuroinflammation that accompanies Alzheimer’s was significantly reduced through NU-9 treatment,” Klein stated. “This drug effectively reduces amyloid beta accumulation as well as the neuroinflammatory consequences that can cause substantial brain damage, demonstrating its multifaceted protective properties at cellular and organismal levels.”
While the researchers are committed to unraveling the precise mechanisms of action for NU-9, they made several key discoveries during their investigation. It was found that NU-9 specifically prevents the accumulation of amyloid beta oligomers within cells, without inhibiting their formation outside of cells. This suggests that NU-9 operates at an intracellular level to thwart the formation of these harmful aggregates.
Further analyses revealed that the efficacy of NU-9 hinges on lysosomes—the cell’s recycling centers—and an enzyme known as cathepsin B. In Alzheimer’s pathology, the lysosomal system is compromised, leading to amyloid beta accumulation. The researchers hypothesize that NU-9 facilitates the transfer of amyloid beta proteins into lysosomes, where cathepsin B assists in breaking down these aggregates.
“Cells utilize two main ‘waste disposal’ systems: the lysosome and the proteasome,” Silverman explained. “Our findings suggest that the proteasome is not involved in this process; rather, NU-9’s action is centered on lysosomal function. However, we are still investigating the specific binding targets of NU-9 that might trigger this lysosomal activity.”
“It remains somewhat enigmatic,” Klein admitted. “It’s akin to a relay race where toxic protein clusters are shuffled between vesicles before reaching the lysosome for disposal. While we have a grasp on the process, pinpointing the precise target of NU-9 remains a challenge.”
Despite the encouraging results, the researchers underscore that much work is still required. Klein emphasizes the importance of extensive memory testing with animal models to validate findings. Additionally, Silverman is focused on optimizing the compound for enhanced effectiveness.
The research team intends to further explore NU-9’s potential in treating other neurodegenerative diseases, including Parkinson’s and Huntington’s diseases.
“Historically, neurodegenerative diseases have been perceived as separate entities, yet our results imply there may be overlapping mechanisms at play,” Silverman remarked. “This insight paves the way for developing a new category of therapeutic agents, akin to NU-9, capable of targeting multiple degenerative diseases at an early stage before significant cellular damage occurs.”
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