"I've been working on Alzheimer's for 30 years and I've never been so excited."
University of Alberta neuroscientist Dr. Satyabrata Kar has spent much of his career trying to understand one of medicine's most difficult diseases. Now research from his team has uncovered a promising new approach that could change how scientists pursue future Alzheimer's treatments.
The researchers found that biodegradable nanoparticles reduced several signs of Alzheimer's disease and improved memory in mice with advanced disease pathology.
What makes the discovery unusual is that the nanoparticles were not carrying medication. The material normally used to deliver drugs appeared to produce benefits on its own.
The findings were published in the peer-reviewed journal Alzheimer's & Dementia.
The delivery vehicle became the treatment
The team worked with PLGA, short for poly(D,L-lactic-co-glycolic acid).
PLGA is a biodegradable material widely used in medicine. It can be formed into particles that carry medications and release them gradually inside the body, and more than 20 medicines are currently delivered using it.
Kar's team used what researchers call native PLGA nanoparticles. That means the particles were not loaded with a drug or attached to another therapeutic substance.
In most medical applications, PLGA is the delivery vehicle. In this study, the vehicle itself appeared to affect the disease.
Memory improved after 28 days
The study involved 8-month-old male 5xFAD mice, genetically bred to develop severe Alzheimer's-like changes in the brain.
At that age the mice already had substantial beta-amyloid buildup and cognitive impairment, which let the researchers test whether PLGA could produce improvements after the pathology was established.
The mice received PLGA continuously for 28 days before completing three different tests of learning and memory.
Researchers reported improvements in spatial learning, recognition memory and short-term working memory. The paper describes the treatment as reversing cognitive deficits in the mouse model.
Examinations of the animals' brains found reduced beta-amyloid levels and deposits, less damage to the connections between neurons, and fewer signs of neurodegeneration. The researchers also recorded reduced oxidative stress, changes in immune and inflammatory activity, and improvements in the processes the brain uses to clear beta-amyloid.
The animals were monitored throughout, with no observable weight loss or abnormal behaviour at the dose tested.
Years of research led to this result
Kar began studying the potential of PLGA nanoparticles in Alzheimer's disease in 2020, and the latest findings build on several earlier studies from his laboratory.
His team has previously shown that PLGA can protect neurons from beta-amyloid toxicity, interfere with the aggregation of tau protein, and help identify amyloid plaques in mouse brains.
A study published in 2022 found that native PLGA reduced Alzheimer's-related pathology and improved object-recognition memory in younger mice.
The new research examined older mice with more advanced pathology. It also used several memory tests and studied a wider range of changes inside the brain.
Kar told the University of Alberta that another laboratory in the United States has reproduced some of his team's findings. That replication has not yet been identified in a separate peer-reviewed publication.
One major challenge remains
The results are encouraging, but the way the nanoparticles were delivered would not be practical as a routine treatment for patients.
The researchers implanted miniature osmotic pumps under the animals' skin and connected them to cannulas leading into fluid-filled ventricles inside their brains. The pumps delivered PLGA directly into the brain for 28 days.
The nanoparticles were not given as a pill or through an ordinary injection.
Delivering treatments into the brain is difficult because of the blood-brain barrier, a protective layer that blocks many substances in the bloodstream from reaching brain tissue.
Direct infusion allowed the researchers to bypass that barrier and determine whether PLGA could work once it reached the brain. The next challenge is finding a safe and practical way to produce the same result.
Kar is now collaborating with other researchers to investigate how the nanoparticles could cross the blood-brain barrier and how their half-life could be extended so they remain active longer.
Why the discovery matters
Alzheimer's disease involves several overlapping processes, including abnormal protein accumulation, inflammation, oxidative damage and the gradual loss of connections between brain cells.
That complexity is one reason developing effective treatments has been so difficult.
Kar's research suggests native PLGA may affect several of those processes at once instead of acting on only one target. The particles reduced amyloid production and deposits while also changing processes connected to inflammation, cellular stress and amyloid clearance.
PLGA is also a material researchers already understand well, because of its long history in drug delivery and other medical products.
Its established medical use does not mean native PLGA is approved or proven as an Alzheimer's treatment. It could, however, give researchers a better starting point than an entirely unknown compound.
The University of Alberta team
Kar is based at the University of Alberta's Centre for Prions and Protein Folding Diseases and is affiliated with the departments of medicine, neurology and psychiatry.
The study's authors are Govindarajan Karthivashan, Shuai Wang, Qi Wu, Abhishek Dahal, Xiuju Li, Danny Galleguillos, Simonetta Sipione, Gopal Thinakaran and Satyabrata Kar. Karthivashan and Wang contributed equally.
The work received support from the Canadian Institutes of Health Research, with additional fellowship support connected to the University of Alberta and SynAD. Kar's related research has also involved the National Research Council Canada's Nanotechnology Research Centre in Edmonton.
What happens next
The discovery remains at the preclinical stage. It has not been tested in people, no human clinical trial has been announced, and no PLGA nanoparticle treatment is available for Alzheimer's disease.
Two things gate any move toward human testing: independent replication of the results, and a delivery method that doesn't require a pump feeding into the brain.
Those steps will take time. Still, after 30 years of studying Alzheimer's disease, Kar believes his team has found something worth pursuing.
Read the research
Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model — Alzheimer's & Dementia
Nanoparticles show potential as new treatment for Alzheimer's — University of Alberta Folio
For information and family support, contact the Alzheimer Society of Alberta and Northwest Territories at 1-866-950-5465.
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