Speeding Brain’s Garbage Disposal Could Slow Alzheimer’s

Rolipram activates the brain’s garbage disposal system, eliminating excess tau proteins (glowing red dots) associated with neurodegenerative diseases such as Alzheimer’s disease. [Laboratory of Karen Duff/CUMC]

Toxic proteins that accumulate in brain cells are ordinarily ground up by the proteasome, the cell’s garbage disposal, unless its operation is impeded by the molecular equivalent of clogs. Then the proteasome slows down, and toxic proteins accumulate, contributing to Alzheimer’ disease and other neurodegenerative disorders. Clogs, a recent study has shown, may occur when the toxic protein known as tau sticks to the proteasome. To remove such clogs, the study has indicated, the addition of a chemical agent may suffice.

The study, conducted by researchers at Columbia University Medical Center (CUMC), used a mouse model of Alzheimer’s in which the clogging mechanism could be demonstrated. After showing that tau sticks to the proteasome and slows down the garbage disposal process, the researchers administered an agent called rolipram. This agent activated the proteasome and restored protein disposal to normal levels. It also improved the memory of diseased mice to levels seen in healthy mice.

Rolipram had been tested before in mice, and it was shown to improve memory. But the mechanism by which rolipram brought this improvement remained unclear. According to the new research, rolipram works by inhibiting the PDE-4 enzyme, thereby producing a physical change in the proteasome that increases its activity.

These findings appeared December 21 in the journal Nature Medicine, in an article entitled, “Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.” The article suggests that rolipram is able to restore proteasome function via activation of cAMP-protein kinase a (PKA) signaling. This activation, the article speculated, probably occurs through proteasome subunit phosphorylation.

“Accumulation of insoluble tau was associated with a decrease in the peptidase activity of brain 26S proteasomes, higher levels of ubiquitinated proteins, and undegraded Ub-G76V-GFP,” the article’s authors wrote. “26S proteasomes from mice with tauopathy were physically associated with tau and were less active in hydrolyzing ubiquitinated proteins, small peptides, and ATP. 26S proteasomes from normal mice incubated with recombinant oligomers or fibrils also showed lower hydrolyzing capacity in the same assays, implicating tau as a proteotoxin.”

Although the researchers were able to activate the proteasome, producing “lower levels of aggregated tau and improvements of cognitive function,” they are not certain of exactly how rolipram worked. Also, they noted that rolipram causes nausea and is thus not a good drug for use in humans.

“We still don't know exactly where the activation is happening, but what's new is that we can modify the proteasome to increase its activity,” said the study's first author, Natura Myeku, Ph.D., an associate research scientist in pathology and cell biology at CUMC. “There could be many other ways to do this.”

This point was reinforced by comments made by the study’s leader, Karen E. Duff, Ph.D., professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.

“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,” noted Dr. Duff. “This has the potential to open up new avenues of treatment for Alzheimer's and many other neurodegenerative diseases.”

Drugs that target proteasomes in this way should work for any disease caused by the accumulation of abnormal proteins, including Alzheimer's, Huntington's, Parkinson's, and frontotemperoral dementia.

“Treatments that speed up these cell disposal mechanisms should, in theory, only degrade abnormal proteins. We don't need to know what the toxic form of the protein is,” Dr. Duff added. “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.”