By: Chen Liang (Lynn Group)
The hallmark of Alzheimer’s disease is the presence of plaques in the brain formed by the aggregation of Aβ peptide with heavy β-sheet content–also known as amyloid. Amyloid is hypothesized to be causative in Alzheimer’s disease through multiple mechanisms such as oxidative stress, interaction with receptors and synaptic loss. Currently, over five million Americans are living with Alzheimer’s disease, costing the nation 236 billion a year. It’s expected that by 2050,healthcare spending on Alzheimer’s will reach one trillion. The NIH invests around 500 million annually for Alzheimer’s research. Despite the prevalence of Alzheimer’s and the intensive efforts of researchers, no effective therapeutics for the disease is yet available. This dilemma attracted me to the study of amyloid as my PhD research project.
Current drug design for Alzheimer’s disease focuses on finding molecules that bind and block the action of these deleterious proteins. Typically, a disease—like cancer, diabetes, and, as some have believed, Alzheimer’s—is caused by proteins with a fixed structure. However, my study in Dr. David Lynn’s lab at Emory University demonstrates that amyloid, unlike conventional drug targets, is highly dynamic and can change structure over time. My research could potentially explain why conventional drug discovery methods don’t succeed with Alzheimer’s –they generally ignore the structural diversity and the changing nature of amyloid.
The peptide I use in this research is the nucleating core of Aβ Dutch mutant, Aβ(16-22)E22Q or KLVFFAQ. People with this genetic mutation develop a more severe form of Alzheimer’s. I discovered that early on, after dissolving, this peptide forms ribbon shaped structures and later autocatalytically change into fibers (Figure 1). More detailed characterization using IE-IR (isotope edited infrared spectroscopy) and solid state NMR (Nuclear Magnetic Resonance) reveals that in the ribbon shape, two neighboring peptides within a β-sheet are pointing in the opposite direction—a state that is commonly referred to as an anti-parallel β-sheet arrangement. Yet the conformation is transient. After a week, the peptides autocatalytically switch into parallel β-sheet where all peptides are pointing in the same direction. Furthermore, by simply adding salt, I was able to control the speed of such shape shifting and even greatly expand the range of observed structures.
This research is significant in the study of Alzheimer’s disease and drug development because it begins to explain why no effective therapeutics have been developed for Alzheimer’s disease. Due to the high thermo-stability of amyloid, researchers commonly assume amyloid structure remains static upon assembly. My study demonstrates the opposite: amyloid can change structure and such a change is sensitive to environmental conditions. Now people can imagine the change and diversity that could occur when amyloid is spreading through different cellular environments as it ravages the brain.
Such an “environmental dependent conformational change” is an important property of Aβ protein and these dynamics are beginning to gain more attention in the scientific community despite being counter-intuitive. Amyloid’s high thermostability has led researchers to reason that once formed amyloid should be stable and their structure should be faithfully replicated throughout the brain. The implication of my study on the treatment of Alzheimer is that instead of measuring the amount of amyloid and treating patients non-discriminately, the structure diversity of amyloids should be central to any consideration in developing diagnostics and therapeutics. New methods of drug discovery—taking into account amyloid’s unique properties—will certainly be necessary for treating Alzheimer’s and the increasing number of amyloid diseases.
Chen Liang et al. “Kinetic Intermediates in Amyloid Assembly.” J. Am. Chem. Soc., 2014, 136 (43), pp 15146-15149. Copyright 2016 American Chemical Society.