Toxic protein clumps damage brain blood vessels in Parkinson’s: Study
Along with neurodegeneration, vascular issues may drive disease progression
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Parkinson's disease involves toxic alpha-synuclein protein clumps damaging both brain cells and blood vessels.
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These clumps weaken blood vessel lining, disrupt the blood-brain barrier, and impair blood flow.
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New 3D lab models and AI aim to develop treatments targeting both neuronal and vascular damage.
In Parkinson’s disease, toxic clumps of alpha-synuclein protein not only damage brain cells but also weaken the lining of blood vessels, with both processes likely working together to drive disease progression, according to a study by researchers from Binghamton University in New York and Drexel University in Philadelphia.
“Parkinson’s is a multifaceted disease,” Jungwook “Jay” Paek, PhD, an assistant professor in Binghamton University’s department of electrical and computer engineering, said in a Binghamton University press release. “Understanding the complex interplay between neurodegeneration and vascular pathology [disease-causing mechanisms] offers unique opportunities to help patients.”
The study, “Microengineering of the capillary interface of midbrain dopaminergic neurons to study Parkinson’s disease vascular alterations,” was published in Communications Engineering.
New findings shed light on vascular complications
Parkinson’s disease causes the loss of dopaminergic neurons, the nerve cells in the brain that produce dopamine, a chemical needed for motor control. Research has long focused on this loss of dopaminergic neurons, but there are also problems with brain blood vessels that are less well understood.
One hallmark of Parkinson’s is the buildup of alpha-synuclein. Normally, this protein helps nerve cells function, but in Parkinson’s, it can misfold and clump into toxic aggregates that damage dopaminergic neurons. Now, the researchers found that they can also damage the blood vessels that supply the brain with oxygen and nutrients through the protective layer called the blood–brain barrier.
“Before this research, most studies on Parkinson’s disease have focused on the aggregation of specific proteins and their impacts on neurodegeneration,” Paek said. “However, how the protein aggregation contributes to vascular complications remains largely underexplored, so this is an exciting finding.”
Researchers create 3D model that mimics part of the brain
To study both nerve cells and blood vessels together, researchers created a three-dimensional lab model that mimics a small part of the brain. This model focuses on the substantia nigra, the region most affected in Parkinson’s. It includes both neurons and tiny blood vessel structures, allowing scientists to observe how they interact.
With this new model, researchers want to offer “a unique tool for developing innovative therapeutic strategies that address both the neuronal and vascular components of [Parkinson’s],” they wrote.
The researchers used organ-on-a-chip technology, which grows living human nerve cells in a small device with narrow channels that act like blood vessels. These devices are about the size of a memory stick but can recreate key features of real organs. This technology enables researchers to study disease-causing mechanisms more realistically than traditional lab-grown cells.
After adding alpha-synuclein fibrils, long chains of misfolded proteins that can trigger other proteins to clump, the researchers observed several changes that match what happens in patients. Nerve cells began to show signs of damage and degeneration, meaning they were slowly losing function and dying. At the same time, there were signs of increased inflammation.
The endothelial cells, which line blood vessels, started to function poorly. The blood-brain barrier itself became disrupted, meaning it was no longer as effective at protecting the brain. Gaps appeared, allowing substances, including potentially harmful ones, to pass through more easily, while blood flow became impaired, reducing the amount of oxygen and nutrients reaching the brain.
“The inside of blood vessels in the brain is covered by endothelial cells that form a protective barrier to prevent harmful substances from entering the brain tissue,” Paek said. “Parkinson’s disease impairs the endothelial barrier functions and causes blood-vessel degeneration. Potentially, that increases neuronal exposure to circulating pathogenic [disease-causing] substances and hurts their function as blood vessels for providing nutrients and oxygen for neurons.”
Looking ahead, the researchers plan to expand this work using models based on artificial intelligence. By better understanding how Parkinson’s develops over time, they hope to support new treatments that target both neuronal and vascular components, rather than focusing on only one mechanism of the disease.
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