Todd Heisler/The New York Times

February 20, 2022

Mapping Interactions of Alzheimer’s-related Tau Protein Reveals Pathway for New Potential Treatments

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The dementia associated Tau protein — known for its role in microtubule regulation — has now been found to also play important roles in the nerve signaling and mitochondrial function in the brain. A Weill Cornell study has discovered that the Tau protein’s role in the neuron goes beyond structural support, creating a novel protein mapping technique that reduces hypothesis bias. 

Li Gan, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute, and her research group took a new approach in creating the Tau interactome –– a comprehensive analysis of Tau protein interactions with other human neuronal proteins for protein interaction discovery.

The Tau protein is known to support the internal skeleton of cells. This network transports nutrients to various parts of the neuron and is therefore vital for keeping the cells alive. Mutations in the Tau gene have been previously shown to reduce nutrients and blood flow in the brain which can lead to neurodegenerative diseases, such as frontotemporal dementia — the death of brain neurons controlling behavior and movement. 

Mutations have also been linked to Alzheimer’s disease —  the death of brain neurons, cells responsible for receiving sensory input which stores or sends motor commands to muscles. This is what eventually leads to memory loss and cognitive decline.

Gan and her team of investigators were able to identify new Tau protein interactions with nerve signal spread and the mitochondria’s production of energy in the brain, which may potentially lead to new treatment targets.

Gan and her colleagues started their research project five years ago when they cultured numerous human neurons that contained the Tau gene and its frontotemporal dementia-causing mutants. Then, they used cutting-edge technology called engineered ascorbic acid peroxidase to label proteins in close proximity and employed mass spectrometry to view protein trafficking. The team then compared how protein interactions in normal and FTD mutants behave.

Gan noted that her team ran into difficulties when objectively analyzing a massive amount of protein data.

“We looked at thousands of proteins and compared different conditions to make sure comparisons are fair, making sure not to exclude any potential artifacts,” Gan said. “The understanding of Tau protein is limited, and we wanted to generate a novel and unbiased hypothesis. That is how we got unexpected results.”

Gan said the results were very surprising.Contrary to beliefs that Tau is a microtubule binding protein, Gan said that her research found that Tau protein is normally associated with signaling proteins released to nearby neurons. This may allow disease-causing Tau proteins to spread to other regions in the brain. 

Tau protein is also associated with mitochondrial proteins and mutations in the Tau gene, which codes for the protein showing a decrease in regular Tau-mitochondrial protein interaction and diminishes mitochondrial operations. This means that neurons in the brain must work harder to make ATP, the main energy-carrying molecule in cells.

These findings have helped expand the current understanding of Tau protein’s role in affecting signaling and energy production of brain cells during diseases. Its newly founded interaction with protein partners may also aid in the development of potential Tau protein-targeted therapy that focuses on its role in the mitochondria and neuron signaling. 

The research team is now investigating how neurodegenerative diseases progress as Tau proteins travel from one synapse to another, which may develop into strategies to combat neurological diseases. They are also studying how Tau mitochondria protein partners contribute to disease. 

These studies may lead to new biomarker developments for mitochondria in human patients that are hard to evaluate by using the energy-deficit linked with mutated Tau protein to assess the mitochondria.

As of now, there has been very little success in the current therapies for neurodegenerative diseases, such as an anti-amyloid antibody drug, which works as a passive immunization against toxic amyloid-β species that destroy nerve cells, leading to loss of memory. 

“Tau [protein] targeted therapy is the next step,” Gan said. “If we don’t understand Tau [protein] partners, then we have a very limited view of the potential therapy.”