Biomedical Frontiers: Fall 1997, Vol.4, No.2
A Model for Alzheimer's Disease

A worm model will allow researchers to work out the role of presenilins normally and in Alzheimer's disease.

Two human presenilin genes associated with Alzheimer's disease can function in a worm model, according to a study by CPMC researchers in the December issue of Proceedings of the National Academy of Sciences. This means that the worms could be used as a model for Alzheimer's, enabling researchers to work out the exact role of the genes in the disease and to screen new drugs.

The researchers looked at the functioning of normal and mutant human presenilin genes in the worm C. elegans. In humans, the genes presenilins 1 and 2 are thought to be involved in Alzheimer's. In a previous study, Drs. Diane Levitan and Iva Greenwald found that the sequence of the worm gene sel-12 was similar to the sequences of presenilins 1 and 2, suggesting that sel-12 mutants could serve as a model for Alzheimer's disease. This made the researchers wonder whether the human gene would "work" in the worm and thereby confirm the inference that sel-12 mutants could serve as an Alzheimer's model.

As it turned out, the answer was yes. Normal copies of the PS1 and PS2 genes functioned well in the worm model, correcting the defects caused by mutated copies of the worm gene. In addition, mutated copies of the human genes did not work as well as the normal copies. Reduced levels of presenilin activity, along with increased activity in another, as-yet undetermined area, may contribute to the development of Alzheimer's disease.

"This new worm model will allow us to work out the normal role of presenilins, which will help us understand the role of presenilins in Alzheimer's disease," says Dr. Greenwald, senior author, associate investigator with the Howard Hughes Medical Institute, and professor of biochemistry and molecular biophysics. "Eventually, there is some possibility that we will even be able to use worms to screen potential new drugs for the treatment of Alzheimer's."

The study was a collaboration among Drs. Diane Levitan, Timothy G. Doyle, Denise Brousseau, and Iva Greenwald of the P&S biochemistry and molecular biophysics department, and Drs. Michael K. Lee, Gopal Thinakaran, Hilda H. Slunt, and Sangram S. Sisodia of Johns Hopkins University School of Medicine.