Malcolm A. Leissring, Ph.D.

Dr. Leissring's research is focused on elucidating the molecular pathogenesis of Alzheimer's disease and other age-related neurodegenerative disorders, as well as the fundamental mechanisms underlying aging itself.

Our primary strengths lie in discovering and characterizing novel drug targets, validating their suitability as therapies in vivo, and developing novel therapies and therapeutic approaches. Towards these goals, we employ a wide variety of experimental methods ranging from the molecular to the organismal.

Our work on Alzheimer's disease is focused on proteases that degrade the amyloid ß-protein (Aß), a neurotoxic peptide that forms the plaques that characterize the disease. This aspect of the disease is quite fundamental yet remains relatively unexplored, consequently inspiring a broad range of experimental lines of investigation. Our activities in this area include the characterization of existing proteases at the cellular, molecular, and enzymological levels; high-throughput screening aimed at identifying modulatory compounds with potential therapeutic value; the discovery and characterization of novel Aß-degrading proteases; and the evaluation of novel therapeutic strategies aimed at increasing proteolytic clearance of Aß.

One Aß-degrading protease our group is especially interested in is insulin-degrading enzyme (IDE). This structurally unusual protease is implicated in the pathogenesis not only of Alzheimer's disease, but also of type 2 diabetes, two of the most highly prevalent diseases in modern society. Towards improving our understanding of IDE's role in both of these diseases, we are engaged in a wide range of cellular and molecular studies, and are actively developing and characterizing several animal models with altered IDE activity. We are conducting large-scale compound screening campaigns, the early results of which have succeeded in identifying small-molecules that can enhance IDE proteolytic activity several fold. Finally, we recently used a rational design approach to develop the first potent and selective inhibitors of IDE. In cells, these novel compounds exhibit multiple anti-diabetic properties, and we are engaged in developing new versions of these compounds that will permit us to evaluate their therapeutic potential in vivo.

Given IDE's fundamental role in regulating insulin signaling?which in turn can regulate aging itself?we are actively investigating whether perturbations in IDE affect the lifespan or healthspan of animals. These studies are currently being conducted in the nematode C. elegans, and will soon be expanded to vertebrate animal models.