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2015 Grants - Gordon
Molecular Therapeutics to Mitigate Inflammation, Tauopathy and Degeneration
Marcia Gordon, Ph.D.
University of South Florida
2015 Zenith Fellows Award
Alzheimer’s disease likely begins long before significant memory loss or other clinical symptoms arise. This phase is thought to be characterized by the accumulation of the protein fragment beta-amyloid and an abnormal form of tau protein. Both amyloid and tau have been associated with toxic brain inflammation. However, different kinds of inflammation appear to have different effects on the two protein types.
Marcia Gordon, Ph.D., and colleagues have been studying how inflammation affects the build-up of either beta-amyloid or abnormal tau in the brains of mice engineered to develop an Alzheimer’s-like condition. For beta-amyloid metabolism, some types of inflammation promoted amyloid clumping, while other types appeared to remove amyloid from the brain. For tau metabolism, all types of inflammation promoted abnormal tau build-up. These findings suggest a process for how Alzheimer’s may progress in the brain. In the earliest stages of disease, beta-amyloid may accumulate and trigger brain inflammation. This inflammation, in turn, may lead to the build-up of abnormal tau and ultimately, the damage and death of brain cells. In further studies, the researchers found that a protein called fractalkine, which is known to dampen brain inflammation, could be used to reduce tau build-up and prevent nerve cell loss in the mice.
Dr. Gordon and colleagues will use their current grant to advance these preliminary results with fractalkine therapy. They will also test six other molecular therapeutics for reducing brain inflammation in mice engineered to develop abnormal tau accumulation in the brain. Their two approaches will be either to inactivate certain proteins that promote inflammation or alternatively, activate certain proteins that hinder inflammation. The researchers will then assess the effectiveness of each therapy on the animals’ tau levels, brain cell health and cognitive behavior. This novel line of research could lead to a precise, drug-based therapy for slowing the progression of Alzheimer’s at an early stage.