In neurodegenerative diseases, certain proteins misfold and clump in the brain. A study of mice reports that aggregated tau—a protein associated with Alzheimer’s disease—can impair the function of cells’ proteasomes, garbage disposals that cells use to break down misfolded proteins. Ramping up the activity of proteasomes with a small molecule overcame this impairment, leading to fewer tau aggregates and improved cognitive function. Natura Myeku of Columbia University and colleagues studied genetically engineered mice that express a tau protein prone to aggregate. Proteasomes isolated from these mice had less protein-dicing activity than those from normal animals. The team thinks that tau gloms on to the complex and disrupts its function. To help proteasomes overcome this disruption, the researchers turned to rolipram, a compound that triggers a pathway that phosphorylates the proteasome, a mechanism known to increase proteasome activity. When given to four- to five-month-old engineered mice, the molecule led to more active proteasomes, fewer tau aggregates, and improved spatial memory, compared with control mice (Nat. Med. 2015, DOI: 10.1038/nm.4011).