By enhancing proteasome function, researchers have been able to lower the levels of tau protein aggregates and improve cognitive function in mice with tauopathies, a class of neurodegenerative disorders.

Alzheimer's disease is the most well-known neurodegenerative disorder where tau dysfunction plays a role. But there are easily a half-dozen tauopathies that vary in some aspects, but share the neurofibrillary tangles that result from tau aggregation.

The ubiquitin-proteasome system is a kind of cellular trash disposal that degrades misfolded and damaged proteins, as well as proteins whose concentrations are too high for a cell's current needs.

Proteasome blockers – Takeda Pharmaceutical Co. Ltd.'s Velcade (bortezomib) and Ninlaro (ixazomib) and Amgen Inc.'s Kyprolis (carfilzomib) – are one class of cancer drugs.

The work now published in Nature Medicine takes the opposite tack. It "describes a new biological pathway by which . . . the proteasome can be enhanced," senior author Karen Duff told BioWorld Today. Duff is professor of pathology and cell biology at Columbia University.

Like many cellular systems, the proteasome "becomes far less functional with aging, but also with disease," Duff said.

Part of the problem is that the system cannot keep up with putting ubiquitin tags on proteins that needs disposal. But in neurodegenerative diseases in particular, many proteins have a ubiquitin tag that contributes to the problem. The proteins seem not just to clump, but "to clump into these proteasomes whose job it is to chew them up," Duff explained.

In their paper, which appeared in the Dec. 21, 2015, online issue of Nature Medicine, Duff and her colleagues used the antidepressant rolipram to increase proteasome activity.

Rolipram, which is FDA approved as an antidepressant but not in clinical use due to its side effects, inhibits the enzyme phosphodiesterase 4. That leads to an increase in the activity of cyclic AMP-dependent protein kinase A (cAMP-PKA).

CAMP-PKA is important for proteasome function, and the authors found that in cell culture, exposing brain slices of tauopathy mice to rolipram increased proteasome function and decreased tau accumulation.

In mice treated with the drug in the early stages of disease, rolipram improved their performance on a memory task. Treatment of older animals with more advanced disease was ineffective.

Duff said that those results could not be directly mapped onto human tauopathies.

"We do feel that this is an approach that's better suited to a less damaged brain than a more damaged brain," she said.

But though treatment with rolipram wasn't "a slam dunk" for mice with more advanced disease, "it's also not the end of the story."

In the paper, the team showed that the proteasome "can become so overwhelmed that it can't be rescued." But Duff noted that in the experiments her team reported in Nature Medicine, "treatment was very short term," and that treatment that lasted longer might work better even in later stages of disease. And slowing down the progression by five to 10 years could already make a huge difference in an age-related disease.

Another factor is that the mouse model the team used "doesn't really have the same time course as human disease," Duff said.

In Alzheimer's disease, for example, tau protein, like amyloid, is elevated before clinical symptoms occur.

Duff said the current studies provide proof of concept. Subject to getting funding, the team would like to do repurposing screens of FDA-approved drugs as well as look for new compounds.

The authors are looking for compounds that specifically improve the health of the synapses, which are the structures that are most badly damaged in tauopathies. Any approach that is specific to synapses, Duff said, "might cut down on side effects."

The authors of the paper said they believe that improving proteasome function could be helpful in diseases where a protein other than tau is aggregating.

Clumping is "a common denominator" in many neurodegenerative disorders, first author Natura Myeku, a postdoctoral associate at Columbia University, told BioWorld Today. "The study was done in a tauopathy mouse, but the implications are vast."

It's "very unusual" to get one mechanism that might be broadly usable for neurodegenerative disorders, Duff added.