In the autopsied brains of individuals who died from Alzheimer’s disease (AD), researchers discovered lower levels of the signaling protein DUSP4. The same decrease was replicated in a laboratory model of AD, where it was found to be linked to learning and memory problems. When brain DUSP4 levels were artificially increased, females, but not males, saw an improvement in their cognitive abilities. Although both sexes experienced drops in amyloid and tau brain levels (hallmarks of AD), only females also had a reduction in neuroinflammation. This might explain why males showed no cognitive improvement. Targeting DUSP4 could unlock a unique therapeutic strategy for treating AD in females.

To maintain a healthy environment, cells must respond to what is happening around them. One of the ways they do this is through cell signaling pathways. When a cell receives information about its environment, it triggers a chain of events that passes information from one protein to the next to elicit a response. When signaling pathways work well, cells are healthy and function properly. The enzyme DUSP4 is one of the proteins involved in a pathway that regulates memory, learning, and the creation of nerve cells and their connections.

When postmortem brain tissue from Alzheimer’s patients was examined, decreased levels of DUSP4 were found. To understand how DUSP4 might contribute to the development of AD and its associated cognitive decline, researchers turned to a mouse model of AD. Like human AD brains, the laboratory model of AD showed a marked decrease in DUSP4 levels.

Amyloid plaques, tau tangles, and neuroinflammation are hallmarks of AD pathology. Artificially raising brain DUSP4 levels in the lab resulted in lower levels of amyloid beta and fewer plaques. It also decreased the amount of tau most likely to form tangles. Interestingly, only females had less activity in pathways that trigger neuroinflammation. This suggests that DUSP4 may play a role in neuroinflammation in females.

Raising DUSP4 levels also restored cognitive abilities in females. While both sexes benefited from lower levels of pathological amyloid and tau, it wasn’t enough to rescue the cognitive impairments seen in males. Reducing neuroinflammation may be the key to the cognitive improvements seen in females.

Women are at a greater risk of developing AD than men, and sex-specific interventions for treating AD will likely be necessary. Targeting DUSP4 and its ability to selectively regulate neuroinflammatory pathways could be particularly effective in treating females affected by AD.

Published in Cells:

Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females

Stephen R. Salton, M.D., Ph.D., Icahn School of Medicine at Mount Sinai

Michelle Ehrlich, M.D., Icahn School of Medicine at Mount Sinai

Sam Gandy, M.D., Ph.D., Icahn School of Medicine at Mount Sinai