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Professor Explores Alzheimer's Causes

August 31, 2006
Massachusetts Institute Of Technology
Some people live to be 100 without falling victim to Alzheimer's disease. Li-Huei Tsai, who joined MIT this spring as Picower Professor of Neuroscience, wants to know why.

Li-Huei Tsai.
Credit: Photo Cynthia Henshall, Picower Institute

Some people live to be 100 without falling victim to Alzheimer's disease. Li-Huei Tsai, who joined MIT this spring as Picower Professor of Neuroscience, wants to know why.

Amyloid beta or Abeta (a protein fragment that accumulates in the brains of Alzheimer's patients) is a telltale sign of the disease, which affects 4 million Americans, most over age 65. Normally, the body manages to break down and eliminate these fragments, but in the aging brain, they tend to form insoluble plaques.

To add to the mystery, some people function relatively normally with plaques nestled among their neurons, while others are virtually incapacitated. "There are people with a significant plaque load who can keep up with their daily lives," said Tsai, who has appointments in the Department of Brain and Cognitive Sciences and at the Picower Institute for Learning and Memory. "Obviously, other factors are determining whether they have full-blown Alzheimer's."

Tsai, who as a child in Taipei witnessed her beloved grandmother's descent into dementia, is determined to unravel the thorny questions associated with neurodegenerative and psychiatric disorders.

Tsai uses a combination of molecular, cellular and biochemical approaches to study Alzheimer's disease and psychiatric and developmental disorders. She focuses on a kinase (kinases are enzymes that change proteins) called Cdk5. Cdk5, paired with the protein p35, helps new neurons form and migrate to their correct positions during brain development. But Cdk5, paired with an aberrant form of p35 called p25, also is implicated in age-related neurodegenerative diseases.

Psychiatric diseases such as schizophrenia and the neurodegenerative diseases of old age are as devastating as they are elusive. Their very intractability is one of the things that attracted Tsai to the field 10 years ago when she abruptly switched from cancer research to neuroscience.

"There are still a lot of unknowns," Tsai said. "I think causes for psychiatric disorders are still very much unclear."

And getting fuzzier. There is no definitive diagnosis for Alzheimer's, and as more sophisticated cognitive tests are developed, the line between whether or not memory loss and personality changes are tied to Alzheimer's becomes more and more blurred.

For the 5 percent of the population with an inherited tendency toward Alzheimer's, genes are the culprit. But for the 95 percent of the aging population in which the disease arises spontaneously, the role of Abeta plaques becomes murkier.

Tsai, along with many other researchers, is eagerly awaiting the results of anti-amyloid studies in humans. A handful of therapies -- based on antibodies, enzymes or preventing plaques from aggregating into characteristic Alzheimer's clumps -- seem to be effective in animal models. "The question is, if you get rid of the plaques, will you prevent Alzheimer's?" Tsai said.

Major pharmaceutical companies are betting heavily that the answer is yes. They all have therapeutics in the pipeline based on one or more of the anti-plaque approaches. But Tsai wonders if eliminating plaques is sufficient to prevent or cure the majority of Alzheimer's cases.

Tsai's laboratory has developed an innovative mouse model that exhibits the onset of Alzheimer's symptoms in a fraction of the time previously possible. She uses this and other techniques to zero in on the trigger of the cascade of events that leads to Alzheimer's.

Tsai believes that a combination of genetic and environmental factors involving a variety of biological systems ultimately underlies Alzheimer's. Treatment, she predicts, will likely be a cocktail of drugs such as the ones used for AIDS and some cancers. Tsai hopes such a treatment based on the fundamental knowledge spawned by her lab will emerge in the not-too-distant future.

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