Cell Biology, Neuroscience
Massachusetts Institute of Technology
Dr. Tsai is also Picower Professor of Neuroscience in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology.
Li-Huei Tsai is interested in elucidating the pathogenic mechanisms underlying neurological disorders affecting cognition. The major research areas in her laboratory include neurodegenerative disease and psychiatric disorders.
Li-Huei Tsai follows her curiosity and passions. She became a veterinarian in Taiwan, her native country, because it was a "childhood dream" and she thought "it would be really cool."
She decided to get a Ph.D., after attending a molecular biology course the now-deceased Nobel Laureate Howard Temin taught at the University of Wisconsin. She was pursuing a master's degree in veterinary sciences, but the idea of using DNA technology to study biological processes just "clicked" for her.
So, as a graduate student and postdoctoral fellow, she used these genetic tools to study cell division to get a handle on the uncontrolled growth of cancer cells. She discovered two new proteins seemingly involved in cell division, Cdk5, and its regulator p35. But as it turned out, Cdk5 did not behave as expected. It only was active in neurons, which do not undergo cell division.
Cdk5's unusual activity led Tsai to a new field: neuroscience. And for the past 15 years, Tsai has been figuring out how Cdk5 and p35 function in the brain, following her findings wherever they take her.
Her first studies, in the early 1990s, revealed Cdk5 and p35's vital importance during nervous system development, when nerve cells are actively dividing and have to move to their correct location to form the complex regions and architecture of the brain. Although nerve cell migration patterns were known at the time of Tsai's work, her Cdk5/p35 findings provided evidence of some of the first molecules responsible for neuronal movement and positioning.
She also genetically engineered a mouse missing the p35 gene. The mice exhibited spontaneous seizures and learning impairment, and an important region in the brain for learning, the cortex, was structurally inverted. These results underscored the importance of the gene in brain formation. More recently, she has begun to investigate Cdk5 and p35's activity in mature brain cells. She has found these proteins help form the nerve cell connections and circuitry underlying some aspects of learning and memory.
Again, these studies have moved her in a new direction: Alzheimer's disease. Chemical cleavage in nerve cells of p35 to a smaller fragment, called p25, may be an early event in neurodegeneration, she hypothesizes. Why nerve cells form p25 and the consequence of p25's presence in brain cells are active areas of research in her laboratory.
Tsai already has shown p25 levels are higher in postmortem brain tissue of patients with Alzheimer's disease than in people without the disease. Also, excess reactive oxygen inside neuronal cells, a toxic condition believed to be an Alzheimer's risk factor, induces p25 to form. Furthermore, beta-amyloid peptides, the main constituent of the plaques in the brains of Alzheimer's patients, increase the levels of p25. Plaques, which are masses of beta-amyloid peptides that accumulate outside of nerve cells, are characteristic of the brains of those with Alzheimer's.
To study how these elevated levels of p25 affect the brain, Tsai created a mouse that allows her to overexpress the p25 gene in the forebrain of an adult animal for varying amounts of time. Certain areas in the forebrain are selectively afflicted in Alzheimer's. She found that animals exposed to high levels of p25 for six weeks had neuronal loss, elevated beta-amyloid levels, and tau-associated pathology. Normal tau proteins help form structural filaments inside of cells. Altered tau proteins form tangles inside the brain cells of Alzheimer's patients.
Unexpectedly, Tsai also discovered that these mice learn better before the onset of neurodegeneration. Their brains also exhibited more synaptic plasticity, the ability of neuronal connections to change strength in response to stimuli. Tsai hypothesizes that Alzheimer's disease may be due to abnormal regulation of the proteins that normally enhance synaptic plasticity. Excess p25 may be a way for the brain to compensate for neuronal insults, she suggests.
Using these p25-inducible mice, Tsai has found that even animals with neurodegeneration and poor memory recall may be able to recover some long-lost memory. Her research has shown that an enriched environment, which provides the animals with companion mice, toys, and treadmills, restored memory in these animals. Also, sodium butyrate, which inhibits removal of the acetyl chemical group from chromatin, the mixture of DNA and protein that forms chromosomes, retrieved long-lost memory in the p25 animals.
Chromatin remodeling was a surprising result, she said. Her research could lead to new types of treatments to improve cognitive ability in patients with advanced Alzheimer's disease. Time will tell. But Tsai's enthusiastic pursuit of the unanticipated will no doubt lead to further advances in neuroscience.