Collaborative NRC studies advance strategies for combating Alzheimer's

- Edmonton, Alberta

A collaborative study between the National Research Council of Canada (NRC) and the University of Alberta has uncovered exciting possibilities for designing and delivering treatment for Alzheimer's disease.

Alzheimer's disease accounts for about 60% of the world's dementia casesFootnote 1. While few drugs address the symptoms of this neurodegenerative disease, so far none has successfully slowed or stopped its progression.

One of the hallmarks of Alzheimer's is an abnormal accumulation of the amyloid-beta (Aβ) protein, which plays an important role in loss of memory and cognition. These proteins can cluster into aggregates that disrupt the brain's normal neuronal functions, and lead to the loss of some neurons. While the brain automatically degrades some of the protein, any that are missed can become toxic.

The NRC and its collaborators have found that biodegradable nanoparticles (PLGA‑NPs) can disrupt such aggregations. In this study, they used biochemical, structural and spectroscopic analyses to show that PLGA nanoparticles can inhibit Aβ aggregation at different temperatures, and measured whether neurons were protected from Ab-induced damage when PLGA was present.

"We used unconjugated PLGA to make very small nanoparticles that target different facets of the Aβ axis and cross the blood brain barrier (BBB) to deliver drugs to the brain," says Dr. Marianna Kulka, Team Leader with the NRC's Nanotechnology Research Centre. "We were also fortunate that the biodegradable polymers we are using have been approved by the FDA and European Medicines Agency, and have already been shown to be an effective delivery vehicle for a range of drugs." This means that any technology based on this polymer will already have safety data and approvals for future clinical testing.

"Because we've been able to work so efficiently and even publish a joint paper, we have the potential to do really great things together that have a lot of impact," adds University of Alberta professor and neuroscientist, Dr. Satyabrata Kar.

Collaboration is key

Each collaborator on the project brings unique expertise and skills to the table. According to Dr. Kulka, she and the NRC's Dr. Jae‑Young Cho and University of Alberta researchers Drs. Satyabrata Kar and Holger Wille investigated whether PLGA nanoparticles interfere with protein aggregation, and whether they have any effects on how neurons function.

Dr. Cho, Research Council Officer, Nanotechnology Research Centre, also contributed his expertise in atomic force and electronic microscopy techniques. "The images we produced showed a direct physical interaction between nanoparticles and proteins, something we can't see under a conventional microscope because they are just too small," he says, adding that the collaboration blended 2 different but essential worlds. "Dr. Kulka's background is biomedical; I'm an engineer but have good knowledge about characterizing the structure of nanomaterials using different methodologies."

Reduction of Aβ1–42 protein accumulation by PLGA nanoparticles revealed by atomic force microscopy (AFM).

Reduction of Aβ1‑42 protein accumulation by PLGA nanoparticles revealed by atomic force microscopy (AFM). This 3D AFM image in height mode shows spherical morphology of unconjugated PLGA nanoparticles with short twist Aβ fibrils and oligomers, molecules that consist of a few repeating units. Amyloid-β (Aβ) fibrils are the main component of amyloid plaques that develop in brain tissue of Alzheimer's disease patients.

He points out that a respectful working environment ensured that disparate team members learned from each other and says it's also an exceptional learning ground for students. "We are training the next generation of researchers to gain expertise in this niche area."

Dr. Kar showed that PLGA nanoparticles not only disrupt protein aggregates, but also prevent the damage these neurons would cause if left untreated and exposed to the aggregates. "With this collaboration, we've been able to look at the aggregates at the nano and cellular scale and bring the entire spectrum into animal models of Alzheimer's disease," he says.

At the outset of this project 2 years ago, Dr. Kar identified the NRC as a collaborator that could help understand the nanoparticles, modify and characterize them, and figure out their interaction with proteins. "The NRC's unique expertise will also allow us to eventually make them in house rather than buying them from outside."

View to the future

Armed with proof of concept that PLGA has unique therapeutic potential in treating Alzheimer's disease, the team can optimize, fine-tune, and make improvements to the study.

Looking ahead, Dr. Dagmar Fischer, an expert in nanoparticle design for pharmacological applications from the Friedrich-Alexander University in Germany, is helping the team fabricate the next generation of polymer nanoparticles for their studies.

Dr. Kulka admits that critical work remains to be done in finding the link between the pathological neurodegeneration seen under the microscope and its correlations to cognitive decline and loss of function. "We must get to that point both preclinically and clinically before this can be celebrated as an effective therapy." This includes doing further research in vitro and in vivo.

With steep hills left to climb in treating Alzheimer's disease, the possibilities uncovered through this collaborative research are an exciting step forward. "The project is very promising, and the help from the NRC is immense," adds Dr. Kar. "Together, we can continue to move this research along with a view to creating new solutions for this devastating disease."

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