The research of Malcolm A. Leissring, Ph.D., 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.
The primary strengths of Dr. Leissring and his research group lie in discovering and characterizing novel drug targets, validating their suitability as therapies in vivo, and developing novel therapies and therapeutic approaches.
Toward these goals, they employ a wide variety of experimental methods ranging from the molecular to the organismal.
Dr. Leissring's work in Alzheimer's disease is focused on proteases that degrade the amyloid-beta (Aß) protein, 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.
In this area, activities by Dr. Leissring and his team 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.
Insulin-degrading enzyme (IDE) is one Aß-degrading protease in which Dr. Leissring's group is especially interested. This structurally unusual protease is implicated in the pathogenesis of not only Alzheimer's disease, but also type 2 diabetes — two of the most prevalent diseases in modern society.
Toward improving their understanding of IDE's role in both of these diseases, Dr. Leissring and his colleagues are engaged in a wide range of cellular and molecular studies, and they're actively developing and characterizing several animal models with altered IDE activity. They are also 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, they 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. Dr. Leissring and his team are engaged in developing new versions of these compounds that will permit them to evaluate their therapeutic potential in vivo.
Significance to patient care
The drugs that Dr. Leissring's lab is developing hold great promise for eventually becoming clinically useful treatments, but considerable work will be need to be completed before they can be used in patients.
The knowledge his laboratory is uncovering about the fundamental causes of age-related diseases helps to inform the development of effective treatments, including the tailoring of individual treatments for diseases that may have more than one cause.
- Career Development Award, American Diabetes Association, 2011-2016
- Research Award, American Health Assistance Foundation, 2009-2012
- Alzheimer's Disease Project Award, GHR Foundation, 2011-2012
- Coins for Alzheimer's Research Trust Fund Award, 2009-2011
- New Scholar in Aging Award, Ellison Medical Foundation, 2006-2010
- Investigator-Initiated Research Award, Alzheimer's Association, 2007-2010
- New Investigator Award, Alzheimer's Association, 2002-2004
- National Research Service Award, National Institute of Mental Health, 1996-1999