BOSTON, MA – A new mouse model developed by Harvard Medical School researchers and reported in the October 30 Neuron may allow scientists for the first time to spotlight two key proteins in a living animal and see how they contribute to the neuronal death and atrophy found in neurodegenerative diseases. The two proteins are dubbed p25 and cyclin-dependent kinase 5 (Cdk5).
"This is an excellent animal model for any therapeutic approach toward p25 and its link to Alzheimer's and similar neurodegenerative diseases," says Li-Huei Tsai, HMS professor of pathology and Howard Hughes Medical Institute associate investigator, the study's lead author. "We know that p25 causes neurodegeneration, and we want to figure out how that mechanism works."
The new model is the latest in Cdk5 research from the lab of Li-Huei Tsai. 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.
The protein p25 is usually not found in healthy brains, but is formed when a stroke or another oxygen-restricting event cuts p35–a beneficial protein found in healthy brains–to form p25, starting a domino effect that leads to neuronal death and malformation. Once present, p25 activates Cdk5 and alters its normally constructive behavior to kill 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.
Tsai's model exhibits the two characteristics researchers want to study: profound neuronal death and tau-associated degeneration. Some forms of the tau protein are associated with neurodegenerative diseases. 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. 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 caused neurofibrillary tangles in the brain, a symptom of Alzheimer's disease. 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 brain cell 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 p25 levels may not have reached the threshold to induce the neuronal death and substantial tau pathology associated with aberrant p25. Without the high levels of accumulated p25 or evidence of neuronal death, these mice are not useful as models of neurodegeneration.
HARVARD MEDICAL SCHOOL
Harvard Medical School has more than 5,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 17 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Hospital, The CBR Institute, Children's Hospital, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, VA Boston Healthcare System.