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Alzheimer's Disease and Developmental Biology Linked Through Single Molecule

Researchers at the University of Pennsylvania Medical Center and other institutions have uncovered a biochemical connection between presenilin, a molecule involved in the development of Alzheimer's disease, and another protein that controls crucial aspects of developmental biology. The findings are likely to lead to a new synergy between the two research areas and important advances in understanding on both fronts in the coming years. Reports on four related studies from the Penn team and three other groups will appear in the April 8 issue of Nature.

"The hope is that work in Alzheimer's disease will help inform people studying aspects of developmental biology about what might be going on in their neck of the woods and vice versa," says Mark E. Fortini, PhD, an assistant professor of genetics and senior author on one of the papers. "Once you find a common connection between two apparently disparate areas of biology, it can be very powerful in turning your eye on candidate ideas you may want to explore from the other discipline."

The scientists think that presenilin is involved in the processing of two proteins called Notch and amyloid precursor protein (APP). Mutations in the genes that codes for presenilin lead to misprocessing of Notch and APP so that the resulting proteins either cannot do their assigned jobs properly or actively damage cells. Problems with Notch disturb normal development in myriad ways and have even been implicated in one form of T-cell leukemia. Misprocessed APP is thought to produce the variant amyloid protein that dominates the plaques characteristic of Alzheimer's disease.

Notch, first discovered in fruit flies just before World War I, is involved in critical intercellular signaling in a wide array of development processes, many to do with the patterning of tissues. As the embryo develops, progenitor cells must differentiate from each other and take up different duties, a process that involves communication and coordination among the evolving cells. Notch signaling helps determine the cell-fate paths that lead to the organization of skin and hair, for example. It is also involved in guiding the development of certain immune cells, so that the optimal balance of cell types in the immune system is achieved. It is this aspect of Notch activity that, when it goes awry, leads to a particular T-cell leukemia.

Notch is a large receptor protein with segments inside the cell and in the membrane at the surface of the cell. When cells commit to become one or another cell type, they present molecules that bind to the Notch receptor on neighboring cells to communicate this fact, so that the neighboring cell can choose an alternate path.

At several steps in its original production and in its signaling activity, the Notch protein is cut by other molecules in a process as yet little understood. The new studies suggest that presenilin may play a role in the appropriate, precise cutting of Notch.

Two genes that code for presenilin were discovered in 1995 by investigators studying a particularly aggressive form of inherited Alzheimer's disease that strikes people as young as 30 years of age. Since then, researchers have worked to understand presenilin's role in this early onset form of the disease, hoping that the information would provide a better understanding of the factors that lead to development of the more common sporadic version of the disease. That work has demonstrated that presenilin mutations lead to the disproportionate formation from APP of a 42-amino-acid amyloid protein variant abundant in Alzheimer's disease plaques. Like Notch, APP is a large protein that spans the cellular membrane.

The process by which the amyloid is produced from APP involves protein cleavages reminiscent of the cutting of Notch, Fortini notes. And it is here - via the shared need for presenilin in the cutting process -- that the new papers show a promising link between the fields of Alzheimer's disease neuropathology and developmental biology.

"What we can learn from the effect of presenilin on the cleavage of Notch may be directly applicable to better understanding APP processing, leading to new insights into the causes of Alzheimer's disease," says Virginia M.-Y. Lee, PhD, a professor of pathology and laboratory medicine and codirector of Penn's Center for Neurodegenerative Disease Research.

"We now see a common theme to what presenilin is doing in development and in Alzheimer's disease," Fortini says. "Presenilin is required for the processing, cutting, and function of critical proteins in both areas, and defects in presenilin can lead to developmental problems in the one case and to neurological disease in the other."

Graduate student Yihong Ye is the lead author on the Nature study from Fortini's laboratory, and Nina Lukinova, PhD, is a coauthor. The work was supported by grants from the National Institutes of Health and the Alzheimer's Association.

The University of Pennsylvania Medical Center's sponsored research and training ranks second in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation -- $201 million in federal fiscal year 1998. In addition, the institution continued to maintain the highest average annual growth rate since 1991 - 13.2 percent -- of the top ten U.S. academic medical centers. Â鶹´«Ã½ releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page (http://www.med.upenn.edu), to the electronic news services Â鶹´«Ã½ (http://www.newswise.com).

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