John Ladias, M.D.
Beth Israel Deaconess Medical Center
Boston, Massachusetts

2003 T. L. L. Temple Foundation Discovery Award

Amyloid precursor protein (APP), the parent molecule of beta-amyloid, extends through the outer membrane of nerve cells like a clove stuck through the skin of an orange. Beta-amyloid, after it is clipped from APP, remains outside the cell. Recently, researchers have begun to focus on the fragment that remains inside the cell, called the APP intracellular domain (AICD). AICD appears to affect cell function in various ways, and may contribute to the development of Alzheimer’s disease.

John Ladias, MD, and colleagues are investigating evidence that AICD interacts with a group of proteins known by their acronyms NumB, JIP1, and KLC. These proteins regulate the transport of the APP parent protein from the areas of cell where it is constructed to its final home in the outer cell membrane. Using advanced X-ray technology, the researchers will “photograph” the interactions of AICD and these proteins. This will allow them to generate three-dimensional models of the protein structures, revealing how they join together and whether they change shape during these interactions. This structural information will aid in designing drugs that affect AICD’s activity, should this protein fragment turn out to play a role in Alzheimer’s disease.