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2015 Grants - Subramaniam
Role of Rheb GTPase in Alzheimer’s Disease Pathways
Srini Subramaniam, Ph.D.
The Scripps Research Institute-Scripps Florida
2015 New Investigator Research Grant
How does the Rheb protein affect the production of beta-amyloid and tau in the brain?
One molecule at the focus of research into treating Alzheimer’s disease is beta-amyloid, a protein fragment that may be toxic to nerve cells and can ultimately accumulate into clumps called plaques, a hallmark of Alzheimer’s disease. Beta-amyloid is produced from its parent molecule, amyloid precursor protein (APP), in a multi-stage process by a series of proteins that act as a “molecular scissors.” One of these proteins is called beta-secretase 1 (BACE1). In studies with mice engineered to develop Alzheimer’s-like brain changes, scientists have found that BACE1 levels are abnormally high in the brain — a factor that may lead to increased beta-amyloid production. However, the exact mechanisms underlying these changes are unclear.
In initial studies, Srini Subramaniam, Ph.D., and colleagues found that a protein called “Ras homolog enriched in brain,” or Rheb, may prevent BACE1 levels from becoming too high in the brain. However, the researchers are unclear exactly how Rheb may regulate BACE1 levels and subsequently the production of beta-amyloid in the brain.
For their current grant, Dr. Subramaniam’s team plans to characterize several regulatory activities of Rheb. They will investigate Rheb’s role in BACE1 and beta-amyloid production. Additionally, they will investigate whether Rheb might affect the development of abnormal tau protein, which forms neurofibrillary tangles, another hallmark of Alzheimer’s disease. The researchers will specifically determine if increasing Rheb protein levels in the brains of Alzheimer’s-like mice lowers the levels of beta-amyloid and abnormal tau and prevents cognitive decline.
The results of this effort could refine our understanding of how beta-amyloid and tau are produced in the earliest stages of Alzheimer’s disease. More importantly, this understanding could identify Rheb as a critical target for disease-modifying therapies.