A new mouse model may provide insight into the molecular activity of two important proteins that contribute to the neuron loss characteristic of neurodegenerative diseases, according to an article in the October 30th issue of the journal Neuron. The two proteins are called p25 and cyclin-dependent kinase 5.
“This is an excellent animal model for any therapeutic approach toward p25 and its link to Alzheimer’s and similar neurodegenerative diseases,” said Dr. Li-Huei Tsai, the study’s lead author. “We know that p25 causes neurodegeneration, and we want to figure out how that mechanism works.”

The mouse model is the latest result from long-term work involving cyclin-dependent kinase 5. Over the past nine years, Tsai and her American colleagues have defined many of the protein’s functions and noted the role that its usual regulator (p35) plays in orienting neuronal migration and growth. Their latest challenge is to understand how cyclin-dependent kinase 5 and p25 lead to neurodegenerative diseases.

The protein p25 is rarely found in healthy brains. It is formed from the normal regulator protein p35 after a hypoxic or anoxic event. This formation of p25 triggers the chain of reactions that lead to neuronal death and malformation. Once present, p25 activates cyclin-dependent kinase 5 such that it loses its normal constructive behavior and becomes neurotoxic.

Because p25 is longer-lived than p35, it accumulates in the brain and continues to act as a neurotoxin. Researchers have noted overactive cyclin-dependent kinase 5 and accumulated p25 protein in the brain tissue of people with Alzheimer’s disease and Niemann-Pick type C.

The value of the current work is the establishment of an in vivo model for study of the neurotoxic effects of the two proteins, overactive cyclin-dependent kinase 5 and p25, in the brain. The model exhibits the two characteristics researchers want to study: profound neuronal death and tau-associated degeneration. Some forms of tau protein are associated with neurodegenerative diseases.

The mice were created with a gene that overproduces p25, but this gene is inhibited in the presence of doxycycline. The mice were conceived and raised for four to six weeks on doxycycline, which allowed their brains to develop normally. After the mice were mature, the researchers activated expression of the p25 gene by removing doxycycline from mouse food.

With this model, brains show a high accumulation of p25 protein, substantial atrophy, progressive neuronal loss, and tau pathology. After only 12 weeks of p25 exposure, the mouse brains were disintegrating, with a 40 percent decrease observed in neuronal density. By 30 weeks after p25 induction, the aggregation of tau proteins caused neurofibrillary tangles in the brain, similar to those seen with Alzheimer’s disease. The brains also showed neurodegeneration and neuronal cell death similar to findings in earlier in vitro work.