The Mystery of Lipoprotein Particles in the Nervous System Revealed

Friday - September 15 2023, 20:18 UTC - 1 year ago

Researchers have developed a technique to identify lipoprotein particles in the central nervous system, which are much more diverse than previously thought. These particles are rich in proteins that affect wound healing, the immune response, and the creation and nurturing of brain cells called neurons. Of the three commonly studied forms of APOE, the form known as APOE4 puts people at higher risk of Alzheimer’s disease. APOE reigns supreme, serving as a scaffold to hold lipids and other proteins. It transports these pathways and collections of molecular collaborators through the nervous system to perform various tasks.

Researchers have developed a technique to identify key fat-filled particles known as lipoproteins within the central nervous system, opening a new view into the workings of the brain.

The study revealed that these particles, molecular cousins of the well-known HDL, or "good cholesterol" particles in our bloodstream, are much more diverse than previously thought. The team identified over 300 distinct proteins linked with these particles, a significant increase from the previously known 16, that fall into at least 10 different families.

These particles are rich in proteins that affect wound healing, the immune response, and the creation and nurturing of brain cells called neurons which are important for cognitive function. The most common protein on the particles is apolipoprotein E, better known as APOE. Of the three commonly studied forms of APOE, the form known as APOE4 puts people at higher risk of Alzheimer’s disease. One copy of the APOE4 gene makes a person approximately four times as likely to develop dementia; a person with two copies is about 12 times more vulnerable.

The results were recently published in the journal Science Advances. The leader of the study is John Melchior, a protein biochemist at the Department of Energy’s Pacific Northwest National Laboratory. Melchior is a leader in lipoprotein research—and a carrier of two copies of the APOE4 gene, adding a personal incentive to his work to understand the protein’s action in the nervous system.

"We’ve known for a long time that in the nervous system, APOE is the primary protein on these particles calling the shots. But we don’t know much more beyond that. Our technology opens the door to learning more," said Melchior.

"What the heck is APOE4 doing? That’s the big question. Why does one form translate to less risk for dementia while a slightly different form confers significant risk? Our technology brings us one step toward more answers," he added.

Lipoproteins are best known for their work in the circulatory system, where they transport fat and cholesterol. It’s easy for scientists to detect HDL and LDL, known to many as "good cholesterol" and "bad cholesterol," in the bloodstream because the molecules there are plentiful.

However, lipoproteins in the nervous system are much scanter, present at less than 1 percent of the concentration in blood. Their actions, even their presence, in the nervous system have been a mystery. Scientists know that these balls of fat and protein wrapped together to travel in the bloodstream and carry out all sorts of important functions, like shuttling cholesterol and nutrients.

On the particles in the central nervous system, APOE reigns supreme, serving as a scaffold to hold lipids and other proteins together. It also transports these nutrient-rich lipids and collections of molecular collaborators—groupings of proteins on its surface—throughout the nervous system to perform their tasks. The proteins are specialized tools that can do things like repair cells, turn genes on or off, or regulate amyloid-beta processing, a well-known molecule related to the development of dementia. The work suggests that APOE may serve as a master key in the nervous system, able to influence a complex web of activities.