How does a specific modification of the tau protein increase its abnormal accumulation and toxic effects on nerve cells?

2016 Mechanisms of Cellular Death in Neurodegeneration Grant



A characteristic of Alzheimer’s and other neurodegenerative diseases is the build-up of a protein called tau in the brain to form tangles. Tau protein, which normally helps nerve cells maintain their proper shape as well as transporting nutrients, becomes modified during Alzheimer’s disease. One type of modification is the addition of a specific molecule, called phosphate, to particular parts of the tau protein. This changes the tau protein shape and can lead to its abnormal build-up into tau 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,” has been seen in mice with Alzheimer’s soon after experiencing a traumatic brain injury. Cis P-tau is also found in the brains of people with Alzheimer’s disease. Researchers believe that this modified tau protein could disrupt nerve cell structure and the transport of nutrients causing nerve cells to die. Research in mice has suggested that an antibody that binds to cis P-tau could 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.

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, ultimately helping researchers to find ways to detect these changes, as well as treatments targeting tau-related nerve cell death in neurodegenerative disease. These are important studies as we currently have little information about why or how nerve cells die in these brain disorders.

Dr Kun Ping Lu and colleagues previously developed a method to study cis P-tau protein from brain tissue. They are using this method to obtain cis P-tau from brain tissue of mice who have experienced traumatic brain injury, and from people who had Alzheimer’s disease. They will examine the purified cis P-tau protein to identify its molecular properties and find any other proteins that it interacts with. Researchers also believe that cis P-tau protein may spread between nerve cells. Therefore, the team is using cells grown in a laboratory dish to study this possibility 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 and point us towards possible new approaches to stop the damage it causes.

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Awarded to
Dr Kun Ping Lu

Beth Israel Deaconess Medical Center, Boston, MA

Full project name
Mechanisms of Neuronal Apoptosis Induced by the Early Pathogenic Cis P-tau

This project is funded through a global funding collaboration, called Mechanisms of Cellular Death in Neurodegeneration (MCDN), between Alzheimer’s Research UK, Alzheimer’s Association and the Weston Brain Institute.