Fabrizio Gardoni, Ph.D.
University of Milan
Milan, Italy

2005 New Investigator Research Grant

One of the hallmarks of Alzheimer’s disease is the accumulation in the brain of a protein fragment called beta-amyloid, which is suspected of disrupting the electrical signals that pass from one nerve cell to another. Beta-amyloid is clipped from the larger amyloid precursor protein (APP) by the sequential action of two enzymes called beta-secretase and gamma-secretase. For these enzymes to work properly, APP must be intact. Because of this, researchers are very interested in the action of a third enzyme, called alpha-secretase, which can cut up APP first, thus preventing formation of beta-amyloid.

Fabrizio Gardoni, Ph.D., and colleagues propose to identify molecules that interact with and perhaps alter the action of alpha-secretase. One aspect of alpha-secretase biology that the researchers will focus on is its cellular location. This is because there are many different, tiny compartments in a nerve cell and depending on where alpha-secretase resides, it might be more or less likely to cut APP.

In particular, Gardoni and colleagues will look at little specialized regions called synapses. This is where chemical signals are passed from one neuron to another. The researchers have previously identified a synapse-associated protein as a partner for alpha-secretase. Now they will study this interaction in cultured cells and in mice. They will examine if the synapse-associated protein can affect the location and activity of alpha-secretase and, in so doing, prevent formation of beta-amyloid. The findings could yield very valuable information about why, where and how beta-amyloid is elevated in the brains of people with Alzheimer’s disease.