Why do you think your paper is highly cited?

Pharmaceutical companies are pursuing a variety of approaches hoping to slow, halt, or reverse the progression of Alzheimer's disease. One approach is to inhibit gamma secretase, one of the enzymes responsible for the production of the Ab peptides that are thought to be involved in the etiology of Alzheimer's disease. Unfortunately, gamma secretase has many substrates and therefore plays important roles in physiology beyond production of the Ab peptides. As a result, gamma-secretase inhibitors have side effects that could limit their potential as treatments for Alzheimer’s disease.

“Our paper was the first to identify key side effects of gamma secretase inhibition such as thymic involution, changes in thymocyte populations and intestinal goblet cell metaplasia, all of which appear to be associated with inhibition of Notch processing by gamma secretase.”

Our paper was the first to identify key side effects of gamma-secretase inhibition such as thymic involution, changes in thymocyte populations, and intestinal goblet cell metaplasia, all of which appear to be associated with inhibition of Notch processing by gamma secretase.

This work also suggested that the potential exists to treat patients with doses of gamma-secretase inhibitors that produce minimal side effects. Because there is so much research effort directed toward identifying and characterizing treatments for Alzheimer’s disease, our paper has attracted wide interest.

This paper not only provides the first detailed description of the side effects of gamma secretase inhibition in animals, but also suggests that doses of gamma-secretase inhibitors that reduce Ab production without side effects can be identified.

Like most pharmaceutical companies, my company (Schering-Plough) has a strong interest in developing drugs that will slow, halt, or reverse the progression of Alzheimer’s disease. In the mid-to-late 1990s, we felt the Alzheimer’s disease research field had matured to the point that tractable drug targets could be identified.

Our aim was to identify drugs that reduce the levels of the Ab peptides, which were increasingly being implicated as being involved in the etiology of Alzheimer’s disease. One of the targets we identified was gamma secretase and, indeed, inhibiting this enzyme has subsequently been shown to reduce levels of the Ab peptides in animals and in humans. The biggest obstacles have been the molecular complexity of gamma secretase, which is a complex of at least four proteins.

Eric M. Parker, Ph.D.
Senior Director, Department of Neurobiology
Schering-Plough Research Institute
Kenilworth, NJ, USA  

A Closer Look...
	Below are images sent in by Eric Parker which correspond with the featured paper, or current research.

Figure 1:

Figure 1: The gamma secretase inhibitor LY-411,575 (1 and 10 mg/kg) reduces plasma (A) and brain (B) Aβ after daily oral administration to CRND8 transgenic mice for 15 days. *P<0.05, ***p<0.001 compared to vehicle.

Figure 2:

Figure 2: The gamma secretase inhibitor LY-411,575 (10 mg/kg) causes intestinal goblet cell metaplasia after daily oral administration to CRND8 transgenic mice for 5 days. Goblet cells appear purple when stained with periodic acid-Schiff stain and are much more numerous after LY-411,575 administration (right figure) than after vehicle administration (left figure).