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PATHOLOGY Mouse Model of Alzheimer's May Clarify Brain Degeneration The working brain is an intricately choreographed ballet with various performers, including nerve cells, proteins, and their regulators. But if one participant makes too many missteps, the entire show may fall apart. In Alzheimer's and other neurodegenerative diseases, just one out-of-step enzyme can lead to the diseases' characteristic brain atrophy and neuron loss. A new mouse model, presented in the Oct. 30 Neuron, may allow researchers for the first time to spotlight the protein cyclin-dependent kinase 5 (Cdk5) in a living animal and see how it leads to neuronal death and atrophy when it malfunctions. Li-Huei Tsai's new mouse model may help researchers decipher Cdk5's and p25's roles in Alzheimer's and other neurodegenerative diseases. (Photo by Steve Gilbert) The new model is the latest in pioneering Cdk5 research from the lab of Li-Huei Tsai, professor of pathology at HMS. Over the past nine years, Tsai and her colleagues have defined many of Cdk5's functions and noted the role its usual regulator p35 plays in orienting neuronal migration and growth. Their latest challenge is deciphering how Cdk5 and the pernicious regulator p25 lead to neurodegenerative diseases. A Tool to Tackle P25 Tsai has high hopes that her model will be useful in this work and other research on Cdk5 and p25. "This is an excellent animal model for any therapeutic approach toward p25 and its link to Alzheimer's and similar neurodegenerative diseases," she said. "We know that p25 causes neurodegeneration, and we want to figure out how that mechanism works." "This is an excellent animal model for any therapeutic approach toward p25 and its link to Alzheimer's and similar neurodegenerative diseases." --Li-Huei Tsai The protein p25 is usually not found in a healthy brain, but is formed when a stroke or similar event triggers the protease calpain to lop off part of p35. When turned on by p25, Cdk5 alters its normally constructive behavior and kills neurons. To make matters worse, p25 is longer-lived than p35, so it accumulates in the brain and continues to keep Cdk5 active. Overactive Cdk5 and accumulated p25 have been noted in the brain tissue of people with the neurodegenerative diseases Alzheimer's and Niemann-Pick type C. But the lack of a mouse model prevented researchers from demonstrating in vivo the effects of Cdk5 and p25 in the brain. Profile of Brain Pathology Tsai's model exhibits the two characteristics researchers want to study: profound neuronal death and tau-associated degeneration that involves the excessive addition of phosphate groups to the tau protein. In the model, Tsai turns on the production of p25 when the mice are mature. The mice were created with a gene that overproduces p25, but this gene is inhibited in the presence of the chemical doxycycline. The mice were conceived and raised for four to six weeks on doxycycline, which allowed their brains to develop normally. Once the mice were mature, Tsai turned on the p25 gene by removing doxycycline from their food. Tsai's model produces the results she expected. The mouse brains show a high accumulation of p25, substantial atrophy, progressive neuronal loss, and tau pathology associated with hyperphosphorylation. After only 12 weeks of p25 exposure, the mouse brains were disintegrating, with a 40 percent decrease in neuronal density. By 30 weeks after p25 induction, the aggregation of tau proteins into abnormal filaments started to appear in the brain. The brains also showed neurodegeneration and neuronal cell death similar to earlier in vitro work. Other labs have created mouse models that overproduce p25 throughout their lives, but these models fail to exhibit high p25 levels and neuronal death. Tsai explains that mice in these earlier models may have found a way to cope with the overexpression of toxic p25 during development, thereby lowering the accumulated p25 levels in their brains. These low p25 levels may not have reached the threshold to induce the neuronal death and substantial tau pathology associated with p25. Without the high levels of accumulated p25 or evidence of neuronal death, these mice are not useful as models of neurodegeneration. --Nicole Giese