Abandoned Antidepressant May Have New Life As Alzheimer’s Drug

A drug that was first developed in the early 1990s as a potential antidepressant but never marketed may have a second life as a Alzheimer’s disease treatment.

The drug, rolipram, was discovered by German drugmaker Schering  (now Bayer Schering Pharma), but ultimately didn’t go anywhere due to its limited therapeutic effect in that role and side effect profile. However, Karen E. Duff, PhD, Columbia University Medical Center and the New York State Psychiatric Institute, and colleagues believe that the drug can activate the brain’s “disposal system” to flush out toxic proteins.

“We have shown for the first time that it’s possible to use a drug to activate this disposal system in neurons and effectively slow down disease,” Duff said in a statement. “This has the potential to open up new avenues of treatment for Alzheimer’s and many other neurodegenerative diseases.”

In the brain, worn out cells must be eliminated with the help of a small molecular cylinder known as the proteasome in order to keep functions running normally. Essentially, the proteasome grinds up old proteins, allowing them to be recycled into new ones. In neurodegenerative diseases like Alzheimer’s, old proteins build up in the brain neurons, an indication the proteasome may be damaged.

In a mouse model of neurodegenerative diseases, tau, a toxic protein often found in the brains of Alzheimer’s patients, attaches to the proteasome, slowing down the disposal process. However, after administering rolipram, the proteasome was reactivated and protein disposal returned to normal levels, the researchers reported in the journal nature Medicine. In addition, it helped improved the memory of the mice.

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.

“Treatments that speed up these cell disposal mechanisms should, in theory, only degrade abnormal proteins,” Duff said. “We don’t need to know what the toxic form of the protein is.”


Duff KE, et al. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med. 2015; doi:10.1038/nm.4011.