CatB found to cut APP at a nonmutated beta-secretase site, which is found in 99% of Alzheimer’s patients, according to a Journal of Biological Chemistry study.
Researchers demonstrated a method to reduce the overproduction of amyloid beta (Aß) peptide in mice. The Ab peptides are cut from amyloid precursor protein (APP) by protease enzymes, which cleave APP at two places: the beta-secretase and the gamma-secretase sites. In Alzheimer’s patients, the Aß peptides bind together to form plaques in brain regions responsible for memory.
In the past, scientists have researched a mutant sequence of beta-secretase, cut by a protease called BACE1, only seen in one extended family of patients in Sweden, the researchers explain.
In the current study, the investigators found that a different protease called Cathepsin B (CatB) works to cut the normal beta-secretase site. This site is present in more than 99% of patients with Alzheimer’s disease. CatB has also been shown to be elevated in brains of people with this disease.
They also tested compounds that inhibit CatB, E64d, and CA074Me in a mouse model of Alzheimer’s disease with the normal beta-secretase site. “After drug treatment, using water maze memory tests, we found that the mice exhibited great improvement in their memory as well as reduced brain levels of beta amyloid,” says research leader, Vivian Y. H. Hook, Ph.D., professor in the School of Pharmacy and professor of neurosciences, pharmacology, and medicine at the School of Medicine at University of California, San Diego.
Dr. Hook worked with scientists at Applied Neurotechnology and American Life Science Pharmaceuticals. The study will be published in the March 21 edition of the Journal of Biological Chemistry and is available online on March 14.
