First Author

Alzheimer's disease typically starts with lapses in memory and culminates in full-blown dementia. Using mice that had suffered considerable neuronal loss to model the disease, Li-Huei Tsai's group at the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, Cambridge, and the Howard Hughes Medical Institute in Chevy Chase, Maryland, shows that an environment with lots of toys improves access to memories that seemed to have been lost. In looking for the mechanism responsible, Tsai and colleagues found that the enriched environment did not increase the number of neurons in the brain, but rather spurred existing neurons to make more connections with other neurons. The change was brought about by specific modifications to the histones — the proteins that help package DNA into chromatin. Tsai tells Nature about the roots of neuronal enrichment.

What made this study possible?

We have a mouse model that develops very severe neuronal loss coupled with deficits in learning and memory. By the time patients with Alzheimer's disease present with clinical symptoms, they already show severe loss. So, to a certain extent, this model mimics the human disease in progress. Also, the symptoms can be induced at specific times by turning on the expression of a transgene in the mice.

What was your most important finding?

We knew that Alzheimer's patients eventually lose long-term memory — they cannot remember their own names or the names of their spouses. We gave our mice a task to learn and waited several weeks for the memory to be consolidated. When we then turned on expression of the transgene for a prolonged period of time, the mice could no longer recall the memory. But when we put the mice in an enriched environment or used drugs to induce histone modifications, the memory came back.

Does that mean that memories are not lost?

This is still an open question in patients. But this study strongly suggests that some memories are not lost, just cannot be accessed. It is possible that by inducing a rewiring of the brain and increasing connectivity, memories can be retrieved once again.

How did you move from biochemistry to neuroscience?

When I was doing my postdoctoral work in a cell-cycle lab, I discovered CDK5, a cyclin dependent kinase highly expressed in postmitotic neurons. That was my foray into neurobiology. In the end it worked out well.