A new study provides a glimmer of insight into how a certain drug combats the buildup of toxic proteins associated with Alzheimer's disease. The researchers identified the mechanism by which the drug rolipram boosts the brain’s "garbage disposal" system and improves cognition in mice models of neurodegeneration. The findings are published in Nature Medicine.
For nearly 44 million people worldwide with Alzheimer’s or a related dementia, their brain slowly ails them: Their memories slip away, everyday tasks become all the more difficult, and mood swings burst forth at any moment. Their neurons and synaptic connections, shaped by years of experience and learning, gradually deteriorate as toxic protein fragments accumulate in the brain. As the condition progresses, sufferers are left in a fog of confusion. To this day, the condition is chronic and incurable.
Now, researchers have discovered that tau – a well-known toxic protein that piles up in the brains of people with Alzheimer's and other neurodegenerative diseases – attaches to proteasomes, inciting a slower disposal process inside the cell.
This is important as proteasomes are molecular machines that clear out abnormal and damaged proteins that can then be recycled by the cell. For this reason, they are often dubbed the “garbage disposal” systems of the brain. When tau sticks to the proteasomes, it hinders this process.
"Something profoundly bad happens to proteasomes in diseases where abnormal proteins accumulate,” said first author Natura Myeku in a statement. “Our work on tau showed that even when proteasomes are removed from the diseased brains they remain defective and can’t chew up proteins compared with proteasome from normal brains."
The drug rolipram, however, stimulates the proteasomes to become more active and to reignite the protein clearing process – it does this specifically by inhibiting the PDE-4 enzyme.
Image: Rolipram stimulates the brain's "garbage disposal" system. The glowing red dots in the left image are excess tau proteins. Credit: Laboratory of Karen Duff/Columbia University Medical Center.
"We have shown for the first time that it's possible to use a drug to activate this disposal system in neurons and effectively slow down disease," said study leader Karen E. Duff from Columbia University Medical Center in a statement. "This has the potential to open up new avenues of treatment for Alzheimer's and many other neurodegenerative diseases."
The authors add that drugs targeting proteasomes in a similar fashion should be able to clear up a variety of unwanted proteins that clog up the neurons of not only Alzheimers patients, but also individuals with Huntington's, Parkinson's and frontotemporal dementia.
"We can actually clear out not just one type of protein, but a number of different proteins,” said Dr. Duff in the video. “We don't need to know what the toxic form of the protein is. In Alzheimer's disease, there are at least four different types: amyloid, tau, alpha-synuclein, and TDP43. A well-functioning proteasome can clear out everything at once."
The researchers note that rolipram – known to have unwanted side effects – is not a cure for Alzheimer’s disease; it is a stepping stone to better drug development that performs similar feats but with fewer side effects.
For more information, check out the video by Columbia University Medical Center below.