Enhancing proteasome activity may prevent dementia

A NIH-funded study of mice shows how proteasomes 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 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., programme director at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

To understand how neurodegenerative disorders affect proteasomes, the researchers 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.

Early treatment with rolipram increased proteasome activity

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 Karen E. Duff, Ph.D., professor of pathology and cell biology at Columbia University.

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 Natura Myeku, Ph.D.