Alzheimer's Disease And Developmental Biology Linked Through Singl...( es communication and coordination among...)

es 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 p
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Contact: Franklin Hoke
hokef@mail.med.upenn.edu
215-662-2560
University of Pennsylvania School of Medicine
8-Apr-1999

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