Boosting Proteasome Function May Prevent Spread of Tau Protein

Findings from a mouse study indicate that proteasome function can be influenced by rolipram, which may help to prevent or slow the progression of tauopathies like Alzheimer’s disease.

The research, supported by the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of General Medical Sciences (NIGMS), was published in Nature Medicine.

Investigators led by Karen E. Duff, PhD, of Columbia University found that tau accumulation in a genetically-engineered mouse model of tauopathy was associated with decreased proteasome activity. A decrease in this activity is linked to a buildup of the toxic protein. The researchers hypothesized that activation of the cyclic AMP (cAMP)–protein kinase A (PKA) signaling pathway may increase proteasome function, in turn helping to eliminate excess tau protein.

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Mice that were given rolipram, which increases cAMP levels, showed increased proteasome function and reduced levels of aggregated tau in vivo. Improvements in cognitive performance were also observed. Notably, the drug appeared to only be effective during the early stages of neurodegeneration, but not during the later stages of tauopathy. The drug had no effect on healthy mice.

“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,” Dr Duff said. “The proteasome system we are studying also degrades proteins associated with a number of other neurodegenerative diseases such as Parkinson’s, Huntington’s, frontotemporal degeneration, and amyotrophic lateral sclerosis. We may be able to apply these findings to other disorders that accumulate proteins.”

The researchers are currently conducting a search of FDA-approved drugs or new compounds that may work similarly to rolipram without the severe side effects associated with the drug.

Reference

1. Myeku N, Clelland CL, Emrani S, et al. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med. 2016;22(1):46-53.
2. Boosting brain’s waste disposal system may slow neurodegenerative disease. NIH Research Matters website. Published January 12, 2016. Accessed January 13, 2016. http://www.nih.gov/news-events/nih-research-matters/boosting-brains-waste-disposal-system-may-slow-neurodegenerative-diseases