Drug boosts brains's 'garbage disposal' to improve memory in Alzheimer's disease

When tau proteins accumulate in the brains of those with Alzheimer’s disease, proteasomes—the brain’s garbage disposal system—slow down. Researchers have now shown that a drug that boosts proteasome function, and reduces tau, can improve memory. Their findings were published online December 21, 2015 in the journal Nature Medicine.

“We have identified a new way to activate the brain’s garbage disposal system, and have shown that we can effectively use a drug to activate this system and slow down disease in a mouse model,” said study leader Karen E. Duff, PhD, Professor of Pathology and Cell Biology (in Psychiatry and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at Columbia University Medical Center (CUMC) in New York, NY.

She added, “This has the potential to open up new avenues of treatment for Alzheimer’s and many other neurodegenerative diseases.”

In healthy individuals, the proteasome system breaks down damaged (misfolded) proteins, including those implicated in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. In the brains of those with Alzheimer’s, accumulation of tau protein is associated with a decrease in proteasome activity.

“Something profoundly bad happens to proteasomes in diseases where abnormal proteins accumulate,” said the study’s first author, Natura Myeku, PhD, Associate Research Scientist in Pathology and Cell Biology at CUMC. “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 proteasomes from normal brains.”

In this study, the researchers administered rolipram, a selective phosphodiesterase-4 inhibitor, which kicked the proteasomes into high gear and restored their ability to dispose of damaged proteins. This effect also improved memory to normal levels in diseased mice.

Rolipram has been tested before in mice and was shown to improve memory. But this new research showed a previously unknown function of the drug—it raised levels of cyclic AMP in the brain and activated protein kinase A, which enhanced proteasome function and reduced the accumulation of tau.

“We have uncovered a mechanism by which we can activate proteasomes,” Dr. Myeku said. “However, we still don’t have a full picture how those changes cause proteasomes to become super proteasomes that are able to remove toxic proteins from the brain. For now, it’s exciting to know that brain proteasomes can be repaired, which will allow us to develop better drugs.”

Rolipram was tested and rejected as an antidepressant in humans largely because it caused significant gastrointestinal side effects, such as nausea. But other drugs that target proteasomes in a similar way should work for any neurodegenerative disease caused by the accumulation of abnormal proteins, including Alzheimer’s, frontotemporal degeneration, Huntington’s, and Parkinson’s, the researchers predicted.

“Even though much work has been done, we still don’t know exactly which form of a particular protein is toxic to the brain,” Dr. Duff noted. “This has made it difficult to develop drugs to treat neurodegenerative diseases. In Alzheimer’s disease, the problem is compounded because several types of abnormal proteins can accumulate in a person’s brain, including amyloid, tau, alpha-synuclein, and TDP43. We think that a well-functioning proteasome will be able to clear out everything at once.”