Boosting brain’s waste disposal system may slow neurodegenerative diseases

The researchers showed that rolipram activates the brain’s garbage disposal system, eliminating excess tau proteins (glowing red dots).Columbia University Medical Center

Several neurological disorders, such as Alzheimer’s disease, are characterized by proteins that accumulate in the brain. One protein, called tau, clumps into twisted threads known as tangles. These are a hallmark of Alzheimer’s disease and several other neurodegenerative disorders known as tauopathies.

Our cells have a waste disposal system that works like a combination garbage disposal and recycler. The system, called a proteasome, is a hollow, cylindrical structure that breaks down defective proteins into smaller pieces. The pieces can then be recycled into new proteins needed by the cell.

A research team led by Dr. Karen E. Duff at Columbia University set out to assess whether abnormal tau buildup might be due to defects in proteasome function. The study was supported by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of General Medical Sciences (NIGMS). Results appeared in the January 2016 issue of Nature Medicine.

The researchers used a genetically engineered mouse model of tauopathy. The mice accumulate tau and develop cognitive deficits. The team found that tau accumulation was associated with decreased proteasome activity. Using a cell culture model, they determined that tau aggregates impair proteasome function.

Proteasome function is activated by a pathway involving protein kinase A and cyclic AMP (cAMP). The scientists hypothesized that activating this pathway might increase proteasome function.

When the genetically engineered mice were given a drug that increases cAMP levels (rolipram), they showed increased proteasome function, reduced aggregated tau levels, and improved cognitive performance. The drug was effective in the early stages of degeneration, but not in the later stages of tauopathy. It had no effect on normal healthy mice.

“These results show, for the first time, that you can activate the proteasome in the brain using a drug and effectively slow down the disease, or prevent it from taking a hold,” Duff says. “The proteasome system we are studying also degrades proteins associated with a number of other neurodegenerative diseases such as Parkinson’s, Huntington’s, frontotemporal degeneration, and amyotrophic lateral sclerosis. We may be able to apply these findings to other disorders that accumulate proteins.”

The researchers plan to search libraries of FDA-approved drugs or new molecules for compounds that work more efficiently than rolipram or activate proteasomes by different pathways.

Speeding up brain’s waste disposal may slow down neurodegenerative diseases

Proteasomes and Brain Cell Death: Using mouse brains, scientists studied the role of the proteasome system in neurodegenerative disorders.Karen Duff, Ph.D., Columbia University.

A study of mice shows how proteasomes, a cell’s waste disposal system, may break down during Alzheimer’s disease, creating a cycle in which increased levels of damaged proteins become toxic, clog proteasomes, and kill neurons. The study, published in Nature Medicine and supported by the National Institutes of Health, suggests that enhancing proteasome activity with drugs during the early stages of Alzheimer’s may prevent dementia and reduce damage to the brain.

“This exciting research advances our understanding of the role of the proteasomes in neurodegeneration and provides a potential way to alleviate symptoms of neurodegenerative disorders,” said Roderick Corriveau, Ph.D., program director at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which provided funding for the study.

The proteasome is a hollow, cylindrical structure which chews up defective proteins into smaller, pieces that can be recycled into new proteins needed by a cell. To understand how neurodegenerative disorders affect proteasomes, Natura Myeku, Ph.D., a postdoctoral fellow working with Karen E. Duff, Ph.D., professor of pathology and cell biology at Columbia University, New York City, focused on tau, a structural protein that accumulates into clumps called tangles in the brain cells of patients with Alzheimer’s disease and several other neurodegenerative disorders known as tauopathies.

Using a genetically engineered mouse model of tauopathy, as well as looking at cells in a dish, the scientists discovered that as levels of abnormal tau increased, the proteasome activity slowed down.

Treating the mice at the early stages of tauopathy with the drug rolipram increased proteasome activity, decreased tau accumulations and prevented memory problems. They found that the drug worked exclusively during the early stages degeneration, which began around four months of age. It helped four-month old tauopathy mice remember the location of hidden swimming platforms as well as control mice, and better than tauopathy mice that received placebos. Treating mice at later stages of the disease was not effective.

“These results show, for the first time, that you can activate the proteasome in the brain using a drug and effectively slow down the disease, or prevent it from taking a hold,” said Dr. Duff, senior author of the study.

Rolipram was initially developed as an antidepressant but is not used clinically due to its side effects. It increases the levels of cyclic AMP, a compound that triggers many reactions inside brain cells. Rolipram works by blocking cyclic AMP phosphodiesterase four (PDE4), an enzyme that degrades cyclic AMP. The scientists found that cyclic AMP levels are critical for controlling proteasome activity. Treating brain slices from tauopathy mice with rolipram, or a version of cyclic AMP that PDE4 cannot degrade, reduced the accumulation of tau and sped proteasome activity.

“We were hoping to show, using rolipram, that increasing cyclic AMP is a pharmaceutical strategy worth pursuing. The suggestion is not that rolipram should immediately go into the clinic but that drugs with mechanisms similar to rolipram should be investigated further,” said Dr. Myeku.

Drs. Myeku and Duff plan to further investigate proteasome activity and the impact of tau and other disease-related proteins on this system for chewing up and clearing out damaged proteins. In addition, they want to search libraries of FDA-approved compounds or new molecules for drugs that work in a similar way to rolipram or activate proteasomes by different pathways.

“The proteasome system we are studying also degrades proteins associated with a number of other neurodegenerative diseases such as Parkinson’s, Huntington’s, frontotemporal degeneration and amyotrophic lateral sclerosis. We may be able to apply these findings to other disorders that accumulate proteins,” said Dr. Duff.    

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