The Persistence of Memory

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Having shed light on the mechanisms driving the progress of Alzheimer's disease, Tsai, who had come to MIT in 2006, wanted to figure out how to fight or even reverse some of the symptoms. She and postdoc Andre Fischer, now at the European Neuroscience Institute in Göttingen, Germany, knew of evidence from other studies that physical exercise and environmental enrichment--such as the addition of companions and toys--increases brain function in mice. So they decided to test what would happen if they tried this technique with their Alzheimer's-like mice.

In one experiment, they trained mice to find and remember a platform submerged within a murky pool. Then they induced the Alzheimer's-like effects. The mice swam aimlessly, unable to locate the spot. But when the researchers moved the mice to a more stimulating environment and then placed them back in the swimming pool, the rodents kicked directly to the platform. Those supposedly lost memories had returned.

Why this worked was a mystery, but Tsai thought environmental enrichment might have affected genes associated with learning and memory. She also knew of a set of enzymes called histone deacetylases, or HDACs, that were believed to suppress the activity of some cognition-related genes. Hoping to mimic the effects of environmental enrichment, Tsai and ­Fischer repeated the swimming experiment--this time injecting mice with drugs called HDAC inhibitors, which blocked these enzymes. They reported in a 2007 Nature paper that the drugs improved cognitive performance in Alzheimer's-like mice, enabling them to recall the location of the platform.

The results imply that restoring seemingly lost memories might also be possible in people. "Even in those patients that seem to lose their memory, we don't think the memory is really erased," she says. Tsai suspects that the massive neuronal die-off damages the brain's circuitry--the wiring that connects different regions. Rather than promoting neuron growth, she says, the new environment and the HDAC inhibitors strengthen synapses and dendrites, boosting connections between regions. In other words, they repair the circuits.

Though she's still leading projects on brain development, as well as on the neuroscience of schizophrenia and other disorders, her ongoing work with HDAC inhibitors has her particularly enthusiastic, since it points to an entirely new way to fight Alzheimer's. That 2007 paper just hinted at the possibilities. "We now have some very exciting observations of one particular HDAC that's responsible for a negative regulation of learning and memory," she says. Targeting that enzyme, she explains, could rewire the broken circuitry and improve cognition in Alzheimer's patients.

"We're very hopeful," she says. "We may have something in the next few years that could be safe and beneficial enough to go into humans." Basic research may remain her first love, she adds. "But if my work can do something for the community or society, I would be so overjoyed."