“We have identified a new way to activate the brain’s garbage disposal system, and have shown that we can effectively use a drug to activate this system and slow down disease in a mouse model,” said study leader Karen E. Duff, PhD, 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 NYSPI. “This has the potential to open up new avenues of treatment for Alzheimer’s and many other neurodegenerative diseases.”
The drug used was rolipram, which causes nausea and thus is not a good drug for use in humans. However, similar drugs do not incur nausea as a side effect and can be potentially tested in clinical trials quickly.
Rolipram activates the brain’s garbage disposal system, eliminating excess Tau proteins (glowing red dots) associated with neurodegenerative diseases such as Alzheimer’
The ubiquitin proteasome system (UPS) degrades misfolded proteins including those implicated in neurodegenerative diseases. We investigated the effects of tau accumulation on proteasome function in a mouse model of tauopathy and in a cross to a UPS reporter mouse (line Ub-G76V-GFP). 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. 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. Administration of an agent that activates cAMP–protein kinase A (PKA) signaling led to attenuation of proteasome dysfunction, probably through proteasome subunit phosphorylation. In vivo, this led to lower levels of aggregated tau and improvements in cognitive performance.
Nature Medicine - Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling
To remain healthy, brain cells must continually clear out old, worn, or damaged proteins, a task performed by a small molecular cylinder called the proteasome. The proteasome acts as a kind of garbage disposal, grinding up the old proteins so they can be recycled into new ones. In neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s, proteins tagged for destruction accumulate in the brain’s neurons, suggesting that the cell’s proteasomes are impaired.
Using a genetically engineered mouse, the researchers first discovered that tau—a protein that accumulates in Alzheimer’s, frontotemporal degeneration, and other brain diseases—sticks to the proteasome and slows down the protein disposal process.
“Something profoundly bad happens to proteasomes in diseases where abnormal proteins accumulate,” said the study’s first author, Natura Myeku, PhD, an associate research scientist in the pathology and cell biology department at CUMC. “Our work on tau showed that even when proteasomes are removed from the diseased brains they remain defective and can’t chew up proteins compared with proteasome from normal brains.”
Administering rolipram activated the proteasome and restored protein disposal. The drug also improved memory in diseased mice to levels seen in healthy mice.
Rolipram has been tested before in mice, and was shown to improve memory. But the new research shows a previously unknown function of the drug that produces a physical change in the proteasome and increases its activity.
“We have uncovered a mechanism by which we can activate proteasomes,” said Dr. Myeku. “However, we still don’t have a full picture how those changes cause proteasomes to become super proteasomes that are able to remove toxic proteins from the brain. For now, it’s exciting to know that brain proteasomes can be repaired, which will allow us to develop better drugs.”
Drugs that target proteasomes in this way should work for any neurodegenerative disease caused by the accumulation of abnormal proteins, including Alzheimer’s, frontotemporal degeneration, Huntington’s, and Parkinson’s.
Dr. Duff noted, “Even though much work has been done, we still don’t know exactly which form of a particular protein is toxic to the brain. This has made it difficult to develop drugs to treat neurodegenerative diseases. In Alzheimer’s disease, the problem is compounded because several types of abnormal protein can accumulate in a person’s brain, including amyloid, tau, alpha-synuclein, and TDP43. We think that a well-functioning proteasome will be able to clear out everything at once.”
“This exciting research from Dr. Duff’s team advances our basic understanding of the proteasome system, provides a way to repair the system when it breaks, and holds the potential to alleviate symptoms of neurodegenerative disorders,” said Rod Corriveau, PhD, program director at the National Institute of Health’s National Institute of Neurological Disorders and Stroke, which provided funding for the study.
SOURCES - Nature Medicine, Columbia University Medical Center