Can the Endosomal Network be Restored to Treat Neurodegenerative Conditions?

The endosomal network is a complex system of many parts responsible for moving endosomes within cells. Endosomes are membrane-bound packages used to transfer material in the cell to destinations such as lysosomes, where it is broken down, or a variety of other locations. Dysfunction in the overall system of autophagy, in which wastes and broken structures are sent to the lysosome for recycling, is a feature of aging and neurodegenerative diseases in particular. The researchers here focus on failure in the endosomal network, and find a way to patch it up a little - though it is unclear as to how far removed their point of intervention is from fundamental forms of damage that cause aging. This approach appears to improve the situation in Alzheimer's disease, probably by allowing cells to somewhat better dismantle the amyloid and tau protein aggregates that are associated with the condition. It is, in any case, an interesting take on the problem of declining autophagy with aging, and may turn out to be relevant in many other tissues and conditions.

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.

Researchers used human brain cells created from stem cells to investigate whether enhancing the function of the endosomal network, in a laboratory setting, would affect amyloid beta and tau protein in these human cells. 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. The findings suggest that targeting defects in the endosomal network, through the discovery of drugs or other therapeutics, such as gene therapy, may be a promising strategy against Alzheimer's disease. "This also suggests that something upstream is affecting the production of amyloid beta and phosphorylated tau independently. So one thing we're going to work on going forward will be to identify what this upstream defect might be and whether it, too, could be a target for new therapeutics to treat Alzheimer's."



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