Scientists from Scripps Florida, led by TSRI biologist Srini Subramaniam, have identified a protein that is a critical regulator of a molecule deeply involved in the progression of Alzheimer's disease. The study shows, for the first time, that levels of this regulating protein (known as Rheb) are lower in the brains of Alzheimer's disease sufferers and that this decrease could be a significant factor in the advance of the disease.
TSRI Assistant Professor Srini Subramaniam
Many believe that the Rheb protein may be active in neural plasticity, the ability of the brain to change in response to learning. The team found that Rheb binds and regulates activity of a molecule known as BACE1, an important enzyme in Alzheimer's disease pathology, establishing for the first time a new molecular link between Rheb and BACE1.
"We found that Rheb regulates BACE1, which is a major drug target in Alzheimer's disease," said Dr. Subramaniam. "Studies of the autopsied brains of Alzheimer's patients have found a significant reduction in Rheb, so it is possible that an increase in Rheb could reverse the buildup of amyloid plaque."
Amyloid plaque is found between nerve cells in the brains of Alzheimer's patients. The study noted that in some genetically modified animal models, an increase of Rheb has already been shown to reduce BACE1 levels and the production of amyloid plaque.
"If we can uncover the mechanism by which Rheb alters BACE1 levels, that would be a very good drug target," said Neelam Shahani, a first author of the study with William Pryor, both research associates in the Subramaniam lab.
The new study indicates that Rheb degrades BACE1 through a number of pathways, but more research needs to be done before drug candidates can be developed. "We're very interested in the disease process and plan to keep moving forward to understand precisely how Rheb regulates BACE1," said Dr. Pryor.