A drug that boosts activity in the brain's "garbage disposal" system can decrease levels of toxic proteins associated with Alzheimer's disease and other neurodegenerative disorders and improve cognition in mice, a new study by neuroscientists at Columbia University Medical Center (CUMC) has found. The study was published in the journal Nature Medicine.
The drug used was rolipram, which causes nausea and thus is not a good drug for use in humans, but similar drugs do not incur nausea as a side effect and could go into clinical trials very quickly,
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, proteins tagged for destruction accumulate in the brain's neurons, suggesting that the cell's proteasomes are impaired.
Using a mouse model of neurodegeneration, the researchers first discovered that tau--a toxic protein that accumulates in Alzheimer's and other brain degenerative diseases--sticks to the proteasome and slows down the protein disposal process.
Administering rolipram activated the proteasome and restored protein disposal to normal levels. The drug also improved the memory of diseased mice to levels seen in healthy mice.
Rolipram has been tested before in mice and was shown to improve memory, but the mechanism for how this occurred was unclear. The new research shows that by inhibiting of the PDE-4 enzyme, rolipram produces a physical change in the proteasome that increases its activity.
Drugs that target proteasomes in this way should work for any disease caused by the accumulation of abnormal proteins, including Alzheimer's, Huntington's, Parkinson's and frontotemperoral dementia.