Enhancing Proteasomal Activity in the Brain as an Approach to Treating Neurodegenerative Diseases
Researchers here demonstrate some of the benefits of enhanced cellular housekeeping in mice, the latest work on a general class of therapies to slow the progression of aging based on producing a state of more diligent cellular maintenance. Maintenance processes of interest include the various systems of autophagy responsible for recycling damaged cellular components, as well as the activities of proteasomes responsible for breaking down damaged or otherwise undesirable proteins. These processes are known to be more active in many of the interventions that extend life and slow aging in animals. Despite interest in this approach there has been little concrete progress beyond the laboratory over the past decade; the research here is similar to a number of past animal studies that have gone little further.
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 suggests that enhancing proteasome activity with drugs during the early stages of Alzheimer's may prevent dementia and reduce damage to the brain.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, 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.
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."
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.