My biological training started as an undergraduate research assistant in the Department of Biochemistry at Fudan University in Shanghai, China. My interest in AD research, however, began during the last year of my Ph.D. program. I decided to develop my research career related to human disease after I obtained my Ph.D. degree at the University of Texas Houston Health Science Center in 1994. In 1995, I started my postdoctoral training in Dr. Dennis Selkoe’s laboratory. Dr. Selkoe is a world-renowned expert in AD, and he encouraged me to examine the biological function of presenilin, the causative gene in a majority of early onset familial AD cases. Initially, we searched for a genotype-to-phenotype relationship by studying AD-causing mutant presenilin in mammalian cultured cells. We found that a variety of mutant presenilins can specifically increase the generation of a 42-residue peptide called amyloid ß-protein, which is the main component of amyloid plaques found in brains of AD patients. As a postdoctoral fellow in Dr. Selkoe’s lab, I carried out two projects in collaboration with Drs. Jie Shen and Michael Wolfe, and results from both studies were published in Cell and Nature. The latter collaboration, to explore whether presenilin is the unidentified gamma-secretase that generates amyloid ß-protein, attracted a tremendous amount of attention from AD researchers. After several years of effort, mounting evidence supports the concept that presenilin carries the active domain of the protease. Presenilin is stabilized by three other essential co-factors into a high-molecular-weight protease complex, the gamma-secretase complex.

This gamma–secretase complex has been shown to cleave at least a dozen biologically important substrates in addition to the precursor of amyloid ß-protein. Although reducing the generation of amyloid ß-protein is one of the most promising approaches to slowing down AD progression, dissecting the molecular details of the presenilin/gamma-secretase complex is necessary for designing specific inhibitors that block amyloid ß-protein production without interfering with the function of the other substrates. In addition, because a protease (presenilin) embedded in the membrane and cleaving a substrate within its transmembrane domain is biologically unprecedented, it is important for us to understand the basic molecular events during presenilin-mediated proteolysis.

Currently, my lab uses both mammalian cell culture and zebrafish as model systems to address the molecular pathways relevant to presenilin biology and their implication in the pathogenesis of CNS disorders. Research activities using zebrafish in the last 30 years illustrate the history of human disease diagnosis in the last century, from observing patients’ physical appearance to genotyping disease-associated alleles. We initiate our projects with forward/reverse genetics and explore new approaches for both zebrafish research and therapeutic applications.

To achieve this, I believe that actively performing experiments on a daily basis is important to pursue our goals. One of my greatest motivations is to see the result of my designed experiments. I clearly remember the moment when I was looking at the X-ray film and suddenly found the accumulation of substrate in cells lacking functional presenilin/gamma-secretase, the first piece of data for figures in our Nature paper. The excitement this result brought to me completely paid off the frustration derived from previous experiments. On average, I performed 100 experiments for each project every year, and less than 10 experiments led to the creation of figures for publication. The rest of the experimental results served as the foundation for novel findings. As bench scientists, most of the time we encounter confusing results, and a major portion of our effort devotes to troubleshooting. As long as we are looking at experimental results with prepared eyes, however, we are ready to embrace a moment of discovery and excitement.

Weiming Xia, Ph.D.
Harvard University
Brigham and Women’s Hospital
Center for Neurology
Boston, MA, USA

Read about Alzheimer’s Disease in ESI Special Topics.