New Scholar Award in Aging
Tae-Wan Kim, Ph.D.
Columbia University

Genetic Studies of Factors Controlling Amyloid Production

Alzheimer’s disease (AD) is the most common form of age-related dementia and one of the most serious health problems in the U.S. Most cases of early-onset familial Alzheimer’s disease (FAD) are caused by mutations in two related genes, known as presenilin 1 and 2 (PS1 and PS2). Deciphering the pathobiology associated with the presenilins provides a unique opportunity to elucidate a molecular basis of AD. It is not yet clear how these mutations lead to dementia in AD patients; however, FAD mutations do lead to an increase in the production of the amyloidogenic peptide Ab42, which is the major component of the plaques found in AD brains. The Ab42 fragments result from cleavage of the amyloid precursor protein (APP) by a g-secretase. The identity of the g-secretase is still unresolved, although presenilins are required for g-secretase-mediated generation of Ab42.  

Our current research is aimed at identifying the genes that are essential for g-secretase activity. Using a novel assay system based on RNA interference (RNAi), we have identified several genes that are required for Ab generation. RNA interference (RNAi) is a phenomenon of sequence-specific, post-transcriptional gene silencing mediated by double-stranded RNA molecules. We are also in the process of screening for gene(s) that are specifically associated with Ab42 overexpression in FAD. Successful completion of our studies will lead to the identification of new cellular proteins responsible for regulating the amyloid-generating enzyme. Novel therapies aimed at regulating g-secretase in order to reduce the production of Ab42 carry great potential as effective treatments for AD.

Contact Dr. Kim.