Mouse Model for Study of Neurodegenerative Proteins

Researchers have established a mouse model that allows them to study two proteins, p25 and cyclin-dependent kinase 5 (Cdk5), which are involved in the neuronal death and atrophy found in neurodegenerative diseases.

The long-lived p25 protein is generated in the brain by proteolytic cleavage of the p35 protein. P25 activates Cdk5, and this combination has been found in the brain tissue of patients with neurodegenerative diseases such as Alzheimer's and Niemann-Pick type C. Investigators from Harvard Medical School (Boston, MA, USA) developed a line of mice with a gene for overproduction of p25. Expression of the gene was suppressed during brain development with doxycycline. The drug was removed when the mice matured, and the effects of p25 overexpression were determined.

Results published in the October 30, 2003, issue of Neuron showed that after only 12 weeks of p25 exposure, neuronal density in the mouse brains declined by 40%. By 30 weeks after p25 induction, aggregation of tau proteins caused neurofibrillary tangles in the brain, along with neurodegeneration and neuronal cell death.

"This is an excellent animal model for any therapeutic approach toward p25 and its link to Alzheimer's and similar neurodegenerative diseases,” explained senior author Dr. Li-Huei Tsai, professor of pathology at Harvard Medical School. "We know that p25 causes neurodegeneration, and we want to figure out how that mechanism works.”




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