While neurodegenerative diseases manifest in different ways, several of these diseases share a major hallmark: misfolded proteins inside brain cells. These proteins accumulate in both Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), disrupting physiological brain function and eventually leading to neuron death. Each condition involves different kinds of proteins; misfolded SOD1 proteins, along with several others, cause ALS, while misfolded amyloid-β oligomers cause AD. But misfolded proteins are involved in both. A new Northwestern University study suggests that an experimental drug could treat both.
ALS Drug Research Fuels AD Innovation
The experimental drug is NU-9, a small molecule compound currently approved by the U.S. Food and Drug Administration (FDA) for clinical trials for the treatment of ALS. Now, a Northwestern University study, published March 3 in the journal Proceedings of the National Academy of Sciences, has demonstrated that the drug improves neuron health in animal models of Alzheimer’s disease, making the drug a promising candidate for future clinical studies.
The research team was led by Northwestern’s Richard B. Silverman, who invented NU-9, along with co-corresponding author William Klein, an expert on AD and a cofounder of Acumen Pharmaceuticals. In previous studies, Silverman and collaborator P. Hande Ozdinler discovered that NU-9 helps cells remove protein clumps and restore neuron function in animal models of ALS. Silverman and Klein wanted to build on that research, exploring whether NU-9 might have a similar effect on the protein clumps characteristic of AD.
Testing an ALS Drug on AD Animal Model Cells
The scientists began by adding a form of amyloid-β, the protein that builds up in Alzheimer’s disease, to hippocampal rat cell cultures. The amyloid-β protein clumps quickly formed and attached to the untreated cells. Next, the scientists treated the cells with NU-9 before adding the amyloid-β. NU-9 significantly reduced the amount of protein buildup within the cells; it also reduced buildup along the cells’ branches, or dendrites. Additionally, the drug had a protective effect, even after it was removed from the treated cells. This was, in essence, the same mechanism observed in animal models of ALS. The drug removed and prevented plaque buildup in both cases.
New Drug Has Promising Results with Whole-Animal Models
After testing NU-9 in cell cultures, the team moved on to the 5xFAD mouse models of AD, issuing an oral dose of the drug. The researchers found that the animals’ performance on memory tests improved. The team also noted reduced brain inflammation in follow-up studies of the 5xFAD mouse model.
How does NU-9 work in both ALS and AD animal models? After further analysis, the researchers concluded that NU-9 relies on lysosomes, a sort of “recycling center” within the cell, along with an enzyme called cathepsin B that contributes to these “recycling” effects. The team theorized that NU-9 might help move harmful proteins into the lysosomes, where cathepsin B then helps break them down to prevent accumulation.
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Although the results are promising, the researchers need substantially more evidence that NU-9 is a viable treatment option for humans. This includes more rigorous memory testing in animal models, as well as future clinical trials. The team also plans to explore the effectiveness of NU-9 on other neurodegenerative diseases that are characterized by protein aggregation, such as Parkinson’s disease and Huntington’s disease.
To evaluate protein aggregation, Scantox Neuro offers several in vitro and in vivo model systems to test your compounds. For the determination of Aβ aggregates, the A4 assay is exclusively licensed to Scantox. For the in vitro analysis of tau aggregation, Scantox Neuro offers a cell-free, high-throughput screening tool. For the analysis of α-synuclein aggregation, in vitro approaches, including monomers, pre-formed fibrils, oligomers, and primary cortical mouse neurons, are available. In vivo, protein aggregation can be evaluated in several rodent models of Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. We are happy to suggest the right model for your target protein.
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