Novato, CA – New drug targets that could someday help doctors treat Alzheimer’s Disease have been identified by Buck Institute for Age Research Professor Vivian Hook, Ph.D.
Dr. Hook and the researchers in her laboratory, in conjunction with a private biotech company, have published a paper in the April 12, 2002 issue of the Journal of Neurochemistry that outlines the discovery. The paper (Beta-amyloid peptide in regulated secretory vesicles of chromaffin cells: evidence for multiple cysteine proteolytic activities in distinct pathways for beta-secretase activity in chromaffin vesicles) builds on previous work in the field demonstrating the role of the enzyme BACE 1 as beta-secretase, a candidate drug target for Alzheimer’s Disease.
The current study hypothesizes that the newly defined cysteine protease targets participate in producing the major portion of the toxic beta-amyloid peptide, which accumulates to form plaques in the brain. Overproduction of beta-amyloid is a key mechanism in the development of Alzheimer’s disease.
Medical science has not yet found an effective treatment for Alzheimer’s, a neurological disease that robs its victims of memory and thinking function. The identification of new target enzymes in the brain marks progress in the effort to identify drug targets required for discovery of drugs to halt the disease before it harms the brain. The effort is important, said Dr. Hook, because the disease currently affects 4 million Americans. Statisticians estimate that by 2050, about 14 million people will have Alzheimer’s. "Alzheimer’s is a major health problem," she said, "Our hope is that these new drug targets will eventually provide significant relief by inhibiting the production of the toxic peptide that causes the harm in the first place."
"The results reported by Dr. Hook and her colleagues are exciting and provocative because they challenge the current notion of Alzheimer's Disease, i.e., that a single proteolytic activity represents the only major pathway for beta-site cleavage of the amyloid precursor protein. These new results suggest the very important possibility that for optimal treatment of Alzheimer's disease it may be critical to address both the constitutive and regulated secretory pathways. Dr. Hook and her colleagues have given us a new piece in the Alzheimer's puzzle and potentially a new approach to treatment," commented Dr. Dale E. Bredesen, President and CEO of the Buck Institute.
In Alzheimer’s Disease, the body produces toxic peptides that accumulate in the brain, forming amyloid plaques and blocking the connections that support memory and understanding. Dr. Hook has been studying beta-amyloid peptides, which are responsible for the plaque-causing protein deposits, for the past eight years of her 20-year career. Using neuronal-like bovine chromaffin cells from an in vivo source as a model, her laboratory team reached an understanding of how the normal amyloid precursor protein (APP) in the brain is cut by secretases into smaller toxic peptides that destroy critical brain functions. The chemical elements that "cut" the proteins might be compared to a pair of scissors, said Dr. Hook. "Remember the old game of Rock, Paper, Scissors?" she said. "We want to find a drug that acts like a rock against those scissors, to block the cutting action of the scissors."
"This paper is important because it provides a novel molecular target to discover drugs to treat AD. Indeed, unlike the beta-secretases that have been recently cloned (BACE), the novel beta-secretase described in this paper preferentially cleaves normal APP to beta-peptide whereas BACE preferentially cleaves the Swedish mutant form of APP. Since 99% of people with AD have normal APP, this novel beta-secretase may be more relevant as a molecular target to discover beta-secretase inhibitors to treat AD than BACE, which is the target of most drugs currently being developed," commented Marie-Francoise Chesselet, MD, PhD, Professor of Neurology at UCLA.
Finding medicines will take time, she said, noting that the development of a new drug takes about 10 years from identification through design, testing and FDA approval. However, the time frame could be shorter with facilitation of resources. "We have not identified a drug yet," she said, "but if these new targets are responsible for producing a significant portion of the toxic beta-amyloid in Alzheimer’s and we find drug inhibitors for these targets that reduce production of beta-amyloid, it is possible that these drugs may provide new therapeutics for treating Alzheimer’s disease."
The Hook laboratory recently started the second phase of the search to prevent the damage of Alzheimer’s. Dr. Hook and colleagues have found that protease inhibitors can be identified with the new targets, and they are developing drug candidates with these new targets. If their efforts lead to potential identification of new drug compounds, preliminary screening would then occur, followed by full drug trials at a pharmaceutical company. Funding for this work was provided under a sub-contract from ActiveSite Biotech of Mill Valley, CA (now known as American Life Science Pharmaceuticals, Inc.) to the Buck Institute from a National Institutes of Health Phase I Small Business Innovation Research program grant. Dr. Hook is a co-founder of ActiveSite Biotech.
The Buck Institute for Age Research is a non-profit organization that conducts clinically relevant research into aging and age-related diseases such as cancer, stroke, and Alzheimer’s. Its mission is to extend the healthy years of life through basic research. At the Institute, a multi-disciplinary group of researchers uses state-of-the-art technologies to understand why we age, and to seek ways to delay or prevent age-related diseases. The Buck Institute is the only free-standing institute devoted to age research in the United States, and one of only three in the world. It is located 20 miles north of San Francisco. For more information, please visit the Buck web site at http://www.buckinstitute.org.
Journal
Journal of Neurochemistry