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2016 Grants - Lu
Mechanisms of Neuronal Apoptosis Induced by the Early Pathogenic Cis P-tau
Kun Ping Lu, M.D., Ph.D.
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
2016 Mechanisms of Cellular Death in Neurodegeneration (MCDN)
How does a specific modification of the tau protein increase its abnormal accumulation and toxic effects on nerve cells?
A characteristic of Alzheimer’s and other neurodegenerative diseases is the accumulation of tau protein in the brain in the form of tangles. Tau protein, which normally helps nerve cells maintain their proper shape and transport of nutrients, becomes modified during Alzheimer’s disease. One type of modification is the addition of a phosphate molecule to specific parts of tau protein. This changes the tau protein shape and can lead to its abnormal accumulation and the formation of tangles.
Traumatic brain injury is an environmental risk factor associated with Alzheimer’s disease. A specific phosphate-modified version of tau protein, called “cis P-tau,” can be found in the brains of mice just hours after a traumatic brain injury. Cis P-tau is also found in the brains of people with Alzheimer’s disease. It is hypothesized that this modified tau protein disrupts nerve cell structure and nutrient transport, leading to nerve cell death. Treating traumatic brain injury mice with an antibody that binds to cis P-tau can signal to the immune system to remove the abnormal tau, and avoid these harmful effects. Cis P-tau thus appears to be a very early indicator of nerve cell death, and a major contributor to the harmful effects of tau protein accumulation in the brain.
Kun Ping Lu, M.D., Ph.D, and colleagues previously developed a method to isolate and purify cis P-tau protein from brain tissue. They will use this method to obtain cis P-tau from brain tissue of mice who have experienced traumatic brain injury, and people who had Alzheimer’s disease. The purified cis P-tau protein will be examined to identify its molecular properties and any other proteins with which it interacts. It is also thought that cis P-tau protein may spread between nerve cells. Therefore, the researchers will study this possibility in cells grown in a laboratory dish and determine if it causes cell death. Finally, the team will inject purified cis P-tau protein into specific regions of the brain in mice to help clarify how cis P-tau contributes to nerve cell death and loss of brain function.
This study may advance our understanding of the link between traumatic brain injury and Alzheimer’s disease. Results from this work may lead to further studies in humans, and ultimately the development of common detection strategies and treatments targeting the mechanism of tau-related nerve cell death in neurodegenerative disease. These are important studies for we have little information on why or how nerve cells die in these brain disorders.