Toxic Molecule May Provide Key For Developing Vaccine Against Degenerative Diseases

UCI molecular biologists Charles Glabe and Rakez Kayed found that small toxic molecules believed to trigger cell damage in these diseases have a similar structure. The study, which appears in the April 18, 2003 issue of Science, implies that these molecules, called toxic soluble oligomers, share parallel functions, which makes them suitable targets for new drugs or vaccines that could halt progression of many degenerative diseases.

“This discovery will help focus attention on what may be the primary mechanism for degeneration and cell death,” said Glabe, professor of molecular biology and biochemistry. “Whatever makes these molecules toxic is likely to be the same for all of the different types of oligomers in the different diseases.”

During the progression of these degenerative diseases, proteins called amyloids accumulate as fibrils and begin to damage healthy cells. Oligomer molecules serve as intermediate building blocks during this fibril formation process, and recent studies have found that these oligomers constitute the toxic element that triggers this cell damage.

In the UCI study, the researchers applied an oligomer-specific antibody to amyloid proteins that have been identified in Alzheimer’s, Parkinson’s, Huntington’s, type II diabetes and prion-related disease. They found that the antibody bound only with the oligomer molecules, but did not bind with the normal amyloid proteins or amyloid molecules in the fibrils. This was true across different diseases, even though the proteins that make up the molecules in these diseases are distinct.

“Antibodies recognize other molecules by a lock and key mechanism,” Glabe said. “If the same lock can be opened by several different keys, you can be reasonably sure that the keys, in this case the amyloid oligomers, have the same shape or structure.”

The UCI research team also found that the oligomer-specific antibody blocked the oligomers’ abilities to kill cultured neuronal cells in all of the protein groups they studied. If the oligomer-specific antibody has the same protective effect in humans, it may be possible to develop a vaccine that will simultaneously protect people against several different degenerative diseases.

“Vaccination has already proven to be effective in preventing amyloid accumulation and loss of neuronal function in animal models of Alzheimer’s disease, but human clinical trials of this vaccine were halted because of inflammatory side effects in a fraction of the patients,” Glabe said. “Our antibody may be able to overcome these problems because it targets only these toxic oligomer molecules and not the normal proteins.”

Assisting in the study were UCI molecular biologists Jennifer L. Thompson and Saskia C. Milton, UCI chemist Theresa M. McIntire, and Elizabeth Head and Carl W. Cotman of the UCI Institute for Brain Aging and Dementia. This work was supported by grants from the Larry L. Hillblom Foundation and the National Institutes of Health.