In May, MetLife Foundation honored the recipients of the 2013 Awards for Medical Research in Alzheimer’s Disease. Yueming Li, PhD, is a member and professor of the Sloan-Kettering Institute and director and professor of the Graduate Program in Pharmacology at Weill Medical College of Cornell University. Lennart Mucke, M.D., is director of the Gladstone Institute of Neurological Disease and Joseph B. Martin Distinguished Professor of Neuroscience and professor of Neurology at the University of California, San Francisco (UCSF). Both men were honored at a scientific briefing and awards ceremony on May 15 in New York. Drs. Mucke and Li each received a $200,000 grant for his institution to further his work, and a personal prize of $50,000.
MetLife established the awards in 1986 in order to recognize and reward scientists who are demonstrating significant contributions to the understanding of Alzheimer’s disease. The MetLife Awards for Medical Research in Alzheimer’s Disease are managed by the American Federation for Aging Research (AFAR), which has been a champion of the cause and supporter of funding for science in healthier aging and age-related medicine.
The awards express the belief that research is the road to understanding and ultimately treating this devastating disease. Recent estimates state that well over 100 million and possibly as many as 200 million people worldwide will be living with Alzheimer’s disease by 2050. Currently, more than 5.5 million people in the U.S. are living with Alzheimer’s disease.
“MetLife Foundation is proud to present our awards to these outstanding researchers, whose work helps bring us closer to finding a cure for Alzheimer’s disease,” said Dennis White, president and chief executive officer, MetLife Foundation. “Doctors Li and Mucke have made significant contributions that have also enabled other scientists to explore promising new avenues of Alzheimer’s disease treatment.”
New Directions in Alzheimer’s Research
Dr. Li’s work demonstrates how an enzyme known as gammasecretase works to produce amyloidbeta, a protein that accumulates as plaques in the brains of people with Alzheimer’s disease. These plaques damage the neurons and connections in the brain. Dr. Li has developed a novel way to study the gamma-secretase complex, a method that is now enabling his lab and others to screen for potential treatments.
Dr. Li, who is a lab head in Molecular Pharmacology and Chemistry Program at Memorial Sloan-Kettering Cancer Center, has made the study of gamma-secretase a primary focus, particularly its role in the pathology of Alzheimer’s disease. In a study published in a 2000 edition of Nature, Dr. Li’s team provided the first compelling biochemical evidence that gamma-secretase activity is triggered by presenilin, a subunit within this complex. When mutated, presenilins can lead to Alzheimer’s disease.
In 2010, Dr. Li’s lab reconstituted gammasecretase and identified presenilin as containing the active site for gamma-secretase. This led to further study, which a number of research teams are now conducting, of the structure and function of gamma-secretase at both the molecular and atomic levels. This provided further proof that gamma-secretase is a potential target for the development of Alzheimer’s disease treatments.
Currently, Dr. Li’s team is focusing its research on modulating gamma-secretase activity in order to alter the processing of amyloid precursor protein, which has been implicated in the development of Alzheimer’s disease, and developing targeted therapies based on this knowledge.
Dr. Mucke’s work has focused on identifying molecular and cellular processes by which small assemblies of amyloid-beta impair cognitive functions. He showed how these assemblies work with tau, another protein that accumulates in the brains of Alzheimer’s patients, to disrupt the activity of brain networks. In addition, Dr. Mucke showed that suppressing the abnormal excitability of these brain networks can reverse cognitive and behavioral decline in animal models of Alzheimer’s disease.
In their lab at the Gladstone Institute of Neurological Disease, Dr. Mucke and his team have made a number of important findings regarding the mechanisms that underlie Alzheimer’s disease. They have also identified new therapeutic approaches for blocking these mechanisms. They proved that the activities of the proteins amyloid-beta, apoE4 and tau, all linked to Alzheimer’s disease, can disturb the communication pathways between brain cells. They further found that the interactions among these proteins play an early role in disrupting the brain’s neural networks.
Dr. Mucke and his team also found that the combined actions of amyloid-beta and tau result in some of the over-stimulation of neurons, which is known to be an early characteristic of Alzheimer’s disease.
The results found by Dr. Mucke led him to initiate experiments designed to determine if blocking abnormal network activity could be a therapeutic approach, an area of great promise in drug discovery. His current focus lies in exploring the role of DNA damage and aging-related factors in cognition, and in translating his lab’s latest findings into potential treatments.
“We have selected these individuals because their work has provided major insights to the field and is likely to lead to new Alzheimer’s disease treatments, which are desperately needed,” said David M. Holtzman, M.D., chair of the MetLife Awards for Research in Alzheimer’s Disease Advisory Committee, which selected the winners. Dr. Holtzman is the Andrew B. and Gretchen P. Jones Professor and Chairman, Department of Neurology, Washington University School of Medicine, and is a previous recipient of the MetLife Foundation Award.