SPECTROSCOPY/PATHOLOGY: Amyloid fibril discovery promises neuropathology insight

Advanced laser spectroscopy has enabled the discovery of a new phenomenon that has implications for the treatment of neurodegenerative disease

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Advanced laser spectroscopy has enabled the discovery of a new phenomenon that has implications for the treatment of neurodegenerative disease: spontaneous refolding of amyloid fibrils. According to Earl A. Zimmerman, MD, Professor of Neurology and Director of the Alzheimer's Research Center at the Albany Medical Center (Albany, NY), the work may offer a unique technique to study the cause and diagnose Alzheimer's Disease. The National Science Foundation-sponsored work was recently reported by Dmitry Kurouski and William Lauro, and their professor, Igor K. Lednev at the Department of Chemistry, SUNY at Albany.1

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Spectroscopy enabled the discovery of spontaneous refolding of amyloid fibrils, which has implications for the treatment of neurodegenerative diseases. (Illustration courtesy Aliaksandra Sikirzhytskaya, SUNY-Albany)

Amyloids are insoluble, fibrous protein aggregates associated with diseases such as Alzheimer's, Parkinson's, Huntington's, and prion diseases, and type II diabetes. For this reason, they are of great interest to researchers. But nobody yet understands the pathology of amyloid diseases. And the standard techniques—x-ray crystallography and solution NMR spectroscopy—display significant limitations when applied to amyloids. "Our method requires no labeling or sample prep," says Lednev. He adds that while a few other research groups around the world are using this method for protein studies, "we are first to introduce this approach to the field of amyloids."

Kurouski discovered the effect quite by accident, according to Lednev. The researchers prepared fibrils according to the method necessary for traditional study, which involves maintaining them in a saline solution at 37°C. Then they tested the fibril study as they transferred the fibrils to a salt-free solution at 25°C. Using deep ultraviolet resonance Raman (DUVRR) spectroscopy, atomic force microscopy (AFM) and postmortem hydrogen-deuterium (H-D) exchange experiments, they witnessed the cores of the mature fibrils partially melting and spontaneously refolding. The discovery was unexpected because amyloids have been considered extraordinarily stable.

Although there is currently no solid understanding of amyloid connection with disease, it is accepted that misfolded proteins are toxic. "This is a hypothesis, but it looks like [toxicity results from] small aggregates of misfolded proteins," says Lednev. Just maybe, the discovery will enable control over aggregate structure—and therefore toxicity.

"A better understanding of the dynamism of amyloid fibrils in the brain in Alzheimer's is a new approach to the molecular pathophysiology of the disease," says Zimmerman. "Presently, there is no single test to detect the disease making an early diagnosis, which limits the study of preventive measures in the early, presymptomatic phase. It is exciting to imagine that a blood test could be developed by [Dr. Lednev's] methods."

  1. D. Kurouski et al, Chem. Commun., 46, 4249 (2010)

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