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Scientists at the University of Alabama, in Tuscaloosa, have outlined new methods for better understanding links between specific proteins and the risks associated with Alzheimer's disease [Science Express, 334 (6061): 1372-77].
In experiments using a series of model organisms, including yeast, microscopic roundworms and rats, the researchers showed how basic mechanisms inside cells are disrupted when a specific human protein, known as the amyloid beta (Aβ) peptide, fails to fold properly. The study also shows the role a second protein (PICALM) can play in modifying the problem.
"By using these yeast models in combination with worms, we really are hopeful of finding a way to understand and maybe combat Alzheimer's disease more rapidly," said co-author Guy Caldwell, PhD, professor of biological sciences.
The research involved scientists from several universities and research institutes, including the Whitehead Institute and Massachusetts Institute of Technology, where lead author Sebastian Treusch, PhD, is affiliated. Dr. Treusch works in the lab of Susan Lindquist, PhD, an expert in cell biology and collaborator with Dr. Caldwell on a grant from the Howard Hughes Medical Institute that funded part of this research.
While the repeated misfoldings of Aβ peptides within the human brain previously were known to trigger neuron death, resulting in Alzheimer's, the underlying mechanisms of toxicity were not understood as well, Dr. Caldwell said.
Properly functioning cells must deliver proteins and chemicals efficiently to other parts of the cell, he explained. The research shows how the Aβ peptide interrupts a specific cellular pathway called endocytosis, preventing the delivery of needed proteins to other parts of the cell. "Understanding what is going wrong inside a cell or which pathways or proteins might be directly linked to the mechanisms involved in Alzheimer's is a much more fruitful strategy for drug development," he said.
Information drawn from the brains of deceased patients who had Alzheimer's also was significant in the effort.
Rapid advances in DNA sequencing methods and human genetic population studies are generating an overwhelming number of leads for researchers. Those studies, taken in combination with advantageous attributes of simple organisms, can reveal basic functions of genes and proteins and can be an insightful combination.
"What this paper shows is that simple systems, like yeast and worms, can be engineered to discern mechanisms that might be associated with complex human diseases," Dr. Caldwell said. "By that we may accelerate the path of discovery for advancing therapeutics for those diseases."
Describing the potential significance of their development in light of the challenges faced in understanding and treating Alzheimer's, the researchers said, "Available treatments are few, and their efficacy is limited. Determining how best to rescue neuronal function in the context of the whole brain is a problem of staggering proportions."
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