A new study published in Stem Cell Reports suggests that if trafficking of cellular proteins in brain cells could pave way for new treatments and even prevention for Alzheimer’s disease.
A compound that enhances the movement of proteins within cells reduced the production of forerunners of two proteins implicated in brain cell death. According to researchers damage to, and destruction of, brain cells underlies this common form of dementia.
Brain tissue from people with Alzheimer’s disease shows clumping of two types of proteins. One, amyloid beta, accumulates outside of brain cells; the other, called Tau protein, collects within the cells. Both of these toxic proteins are thought to cause the brain-cell death seen in Alzheimer’s. Recent research suggests that these proteins accumulate because of a defect in the system that ferries proteins within the cell. The proteins are shipped in membrane-bound packages, called endosomes.
The system that shuttles them around the cell is the endosomal network. For proteins to be properly processed, eliminated or recycled, this system must function correctly.
In the new study reported this week, the UW Medicine-led research team used human brain cells created from stem cells. The results showed that a compound that boosts the function of the endosomal network significantly cuts the production of both amyloid beta and a precursor of the Tau protein.
In the study researchers obtained skin cells from patients with Alzheimer’s disease and from patients who had no signs of dementia. Because all of a person’s cells share the same genome, the skin cells from patients with Alzheimer’s would contain the same genetic mutations that affect the patients’ brain cells.
The researchers then “reset” the skin cells by reprogramming them to act as stem cells. Such cells, called induced pluripotent stem cells, are capable of developing into any cell type. The team was thereby able to create neurons that had the same genetic makeup as patients from whom they had collected skin samples.
The lab-grown cells from the Alzheimer’s patients would have the same tendency to generate the excess amount of amyloid beta and the Tau protein precursor that is seen in the brains cells of people with the disorder. This made it possible for the researchers to measure amyloid beta and Tau protein production in these stem cell-derived neurons.
The scientists tested a compound that had been shown in animal studies to stabilize and boost the function of a protein assembly called the retromer. The retromer is a key player in directing how the endosomal “packages” are shuttled about in the endosomal network to be delivered to the right destination.
The researchers found that the compound, called R33, did enhance the function of the retromer. This led to considerable reduction in the production of both the amyloid beta and the form of tau protein that readily aggregates, phosphorylated-Tau.