By Gail Gallessich

A completely new approach to the study of Alzheimer’s disease, initiated by a UCSB chemistry professor, may provide a critical piece in the puzzle of the disease. This tragic neurological illness progressively erases memory in its victims. The key to the new approach is understanding the way certain proteins in the brain fold, or rather “misfold.”

Michael Bowers, professor of chemistry and biochemistry, developed this project, which is being funded by the National Institutes of Health. Bowers’s laboratory will receive $1.3 million of a total $9-million grant, plus biological samples worth an additional $500,000. The grant covers a five-year period. Four institutions are involved.

Bowers is using specialized chemical research methods and applying them to biology. His research will depend upon the study of rare peptides, or strings of amino acids, that are difficult to produce. These will be provided by co-investigator David Teplow, a professor at UCLA’s David Geffen School of Medicine, who has been involved in Alzheimer’s research for over 10 years. Joan-Emma Shea, UCSB professor of chemistry and biochemistry, heads the theoretical modeling aspect of the project.

“Until about five or six years ago, everyone assumed that the large amyloid plaques, or neurofibrillary tangles, that were found in the brains of Alzheimer’s victims were the cause of the disease,” said Bowers. “However, recent scientific discoveries indicate that these large, insoluble aggregates might merely be markers––they do not cause the disease. Rather, smaller soluble oligomers, or peptide complexes, are now felt to be the causative agents, and I find that very interesting.

“In biology, structure and function are tightly coupled,” said Bowers. “When it became clear that small, soluble oligomers were most probably the toxic agents, I realized our ion mobility methods could contribute, since we could measure the oligomer distribution and shapes of these peptides for the first time. “

Because of their expertise, Bowers and his research group are able to track the molecular level changes that lead to development of the disease. They have also begun to clarify the protein aggregation process that causes the plaque.

He described his approach as a new way to determine the structure and composition of the Abeta 42 peptide and its oligomers that are primarily responsible for Alzheimer’s disease. The research team is analyzing the way this peptide folds, causing it to aggregate and disrupt neuronal function.

The goal is to find non-toxic drugs that will interrupt the aggregation process. “If we can do that, we can stop the disease,” said Bowers.

Three years of preliminary work convinced the National Institutes of Health to provide funding. “In the last several months, I believe we have uncovered the identity and shape of the primary toxic oligomer,” said Bowers. “Our results are consistent with (published) findings on transgenic mice, indicating that soluble oligomers with masses matching those we have identified have been extracted from the brains of diseased animals.”

The transgenic mice that Bowers refers to are laboratory mice that have had the gene that creates the Abeta 42 precursor protein spliced into their genome. This process has been shown experimentally to produce memory loss in the animals.

Besides Alzheimer’s disease, Bowers and his group are currently investigating proteins involved in Parkinson’s disease and transmissible spongiform encephalopathies, or “prion” diseases. In the latter, the British government is funding an ante-mortem test for the bovine prion disease, usually called “mad cow” disease. The same test, if successful, should also work on deer and elk.

In addition to Teplow and Shea, co-investigators on the Alzheimer’s project include Gal Bitan, assistant professor at UCLA’s David Geffen School of Medicine; Eugene Stanley, physics professor at Boston University; and, George Benedek, physics professor at MIT.