Results from studies in the lab of Li-Huei Tsai suggest that "memory loss" may be an inaccurate description of certain mental deficits associated with neurodegnerative diseases.

Li-Huei Tsai recalls a life-shaping event when she was a toddler living with her grandmother in Taiwan. "Every morning we took a short walk to the local market for groceries. One day, on the way back, there was a thunderstorm, so we took shelter in a little shed. After the rain, I said, 'Let's go home now.' I looked at my grandmother's face and it was completely without expression. 'Home?' she asked. 'Where is home?'"

Mystified and frightened at the time, Tsai came to understand that her grandmother, then in her 50s, probably had early-onset Alzheimer's disease, a heritable form of the mind-robbing illness that strikes victims in the prime of life. Now an HHMI investigator at the Massachusetts Institute of Technology (MIT), Tsai's mission is to end Alzheimer's disease. "That memory and others like it," she says, "are a big source of my inspiration to carry out this line of research."

Four years ago, her research team created a powerful mouse model that, unlike most previous models, shows the hallmarks of human Alzheimer's disease: massive loss of neurons, the presence of neurofibrillary tangles, and accumulation of amyloid peptides in the brain, accompanied by severe memory loss. What's more, the extensive and rapid brain deterioration in the mice can be quickly turned on and off. "These two characteristics render the mice ideal for looking for potential therapeutics," Tsai says.

Her recent studies focus on a class of enzymes called histone deacetylases (HDACs), which perform many functions in cells and derive their name from their ability to remove small chemical tags, called acetyl groups, from histone proteins—key components of chromosomes. Because histone acetylation patterns can influence gene expression, HDACs have widespread physiological consequences, including in Alzheimer's disease, as Tsai's team first reported in the online version of Nature last April. They were investigating a well-described but poorly understood phenomenon called "fluctuating memory," in which even advanced-stage Alzheimer's patients suddenly regain, at least for a short while, seemingly long-gone remembrances. Caretakers have noted that immersing Alzheimer's patients in intellectually stimulating environments tends to evoke these lucid moments.

Remarkably, Tsai and her colleagues observed the same phenomenon in the lab. After inducing Alzheimer's disease in mice that had been taught a battery of learning and memory tasks, they found that those housed in cages with toys and other intellectual stimulation regained "lost" memories of their acquired skills, but the lessons learned by those kept in spartan cages remained forgotten.

Photo: Matt Kalinowski

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