Tragic Mysteries of the Brain
Engineers join interdisciplinary teams to disentangle the complexities of Alzheimer’s.
By Rosemarie Wesson with M. Lane Gilchrist
For decades, researchers have struggled to find ways to prevent or cure Alzheimer’s disease, a progressive, degenerative disorder afflicting more than 5 million Americans. Alzheimer’s attacks the brain’s nerve cells and results in behavioral changes and loss of memory, thinking, and language skills. The nature of the disease and its causes, processes, development, and consequences is staggeringly complicated. But now, thanks in part to advances in imaging, computational tools, data analytics, and monitoring technologies, researchers are gaining an improved understanding of Alzheimer’s. Their work offers a prime example of collaboration among engineers, biologists, chemists, and physicians—working across institutions, funding agencies, and countries—that promises breakthroughs in fighting complex diseases.
About a year ago, for instance, Toronto-based researchers were able to reverse some of Alzheimer’s symptoms in mice using magnetic resonance-guided ultrasound. More recently, an interdisciplinary 10-member team of researchers from Johns Hopkins University, the National Institute on Aging (NIA), and institutions in Taiwan and Canada drew on data involving 1,394 Baltimore Longitudinal Study of Aging participants to explore a link between Alzheimer’s and being overweight. They found that an increase in body mass at age 50 hastened the disease’s onset and was associated with greater levels of both more amyloid deposits and neurofibrillary tangles, both signs of Alzheimer’s. Engineers at North Carolina State University use computer simulation to study protein aggregation, which is associated with Alzheimer’s and other neurodegenerative diseases.
The City College of New York has been engaged since 2008 in a collaboration with the Memorial Sloan Kettering Cancer Center to study the link between Alzheimer’s and the gamma-secretase enzyme. One of the most complex enzymes, gamma-secretase exists throughout the body. In the brain, for poorly understood reasons, a subset of the protein fragments termed beta-amyloid forms into neurotoxic plaque formations, leading to degeneration and Alzheimer’s. Improved understanding of how it works could lead the way to disease-fighting inhibitors. The researchers built on previous breakthrough research on gamma-secretase by Sloan Kettering biochemist Yueming Li, who partnered with a Grove School of Engineering team led by M. Lane Gilchrist, an assistant professor of chemical engineering.
Engineering proved to be important from the outset, when researchers sought to recreate the enzyme’s natural habitat—an intact cell membrane. Cell membranes are soft and unstable, and are therefore very difficult to study individually. This problem was solved when researchers, using microspherical silica particles, assembled molecules in a mechanically stable structure more suitable for imaging and analysis.
With the advent of modern methods of quantifying genetic mutations, specific changes in the gene that codes for a subunit of the enzyme gamma-secretase were correlated with early-onset Alzheimer’s disease. It was later found that this enzyme cuts longer protein chains to form smaller fragments, some with specific roles in cell physiology and others just as breakdown products for the cell to recycle.
The work was funded by the National Cancer Institute’s U54 program, an initiative that develops partnerships between minority-serving institutions and leading cancer centers. The U54 grant effort was lead by Sloan Kettering behavioral psychologist Tim Alves and CCNY molecular biologist Karen Hubbard. This grant has helped to create many new cross-city collaborations that address health disparities through research, training, and community outreach.
Research on gamma-secretase continues. With funding from the National Institutes of Health, the Gilchrist/Li collaboration has developed a new method to probe and image the enzyme using flow cytometry and fluorescence microscopy in tandem. Bringing these technologies to bear on systems such as gamma-secretase continues to open new avenues of investigation—offering hope to future generations of elderly.
Rosemarie Wesson, Ph.D., is associate dean for research at the Grove School of Engineering, City College of New York, where M. Lane Gilchrist, Ph.D., is an assistant professor of chemical engineering.