Protein interaction map of dementia may point to new targets

By mapping all the protein interactions of a dementia-related protein in the brain called Tau, a team of researchers from Weill Cornell Medicine has created a roadmap to identify potential new treatment targets for Alzheimer’s disease and related dementia.

The Tau protein has long been implicated in neurodegenerative diseases. Mutations in the gene that codes for the Tau protein lead to neurodegenerative diseases such as frontotemporal dementia, while in Alzheimer’s disease the protein accumulates and becomes toxic. But the exact role of the tau protein in these diseases has remained a mystery.

To help solve this mystery, lead author Dr. Li Gan, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute, and colleagues have created a comprehensive atlas, called the Tau interactome, that maps all interactions of the Tau protein with other proteins in human neurons. grown in the laboratory. The results, published on January 20 in the journal Cell, reveal that mutations that decrease interactions between Tau and mitochondrial proteins can impede energy production in the brain, the body’s most energy-intensive organ. Additionally, they found that Tau interacts with proteins in synaptic sites that send electrical signals to other neurons, which may provide clues as to how toxic Tau protein spreads in brains with the condition. Tau.

“Tau is central to neurodegeneration, and understanding how it causes toxicity and cognitive decline has the potential to lead to new therapies to treat dementia,” said Dr. Gan, who is also Burton P. and Emeritus Professor Judith B. Resnick. in Neurodegenerative Diseases at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.

In normal and diseased neurons, the Tau protein forms physical interactions with specific proteins to participate in various neuronal functions. To develop an atlas that maps the interactions altered by pathogenic mutations and neuronal activity, Dr. Gan and his colleagues cultured human neurons from induced pluripotent stem cells that carry the normal Tau gene or the Tau gene with mutations. that cause frontotemporal dementia. They used a technique called quantitative affinity purification mass spectrometry (AP-MS), which allows the study of protein interactions, to compare the behavior of normal and pathogenic Tau mutants. To capture how neuronal activity alters the Tau interactome, they used cutting-edge technology called ascorbic acid peroxidase (APEX) to tag proteins near Tau in milliseconds.

“The combination of two highly quantitative proteomics technologies has allowed us to establish Tau interactions with unprecedented spatial and temporal resolution in human neurons,” said Dr. Gan, co-founder with equity and consultant for Aeton Therapeutics, Inc.

Unexpectedly, the team discovered that Tau interacts with proteins that are released in synapses that send signals to nearby neurons. This may allow pathogenic versions of Tau to spread from one brain region to another and help explain the phenomena that neurons trigger together often die together, Dr. Gan said.

Another surprising discovery is that they found that Tau proteins have strong interactions with many proteins in the energy-producing mitochondria of neurons.

“A growing number of studies link dysregulated energy metabolism to neurodegeneration, but the mechanism remains elusive,” she said. “We found that pathogenic mutations reduce tau-mitochondrial protein interaction and impair mitochondrial function.”

When they analyzed patient data from the Accelerating Medicines Partnership – Alzheimer’s Disease (AMP-AD), Dr. Gan and his team found that patients with Alzheimer’s disease had lower levels of proteins interacting with Tau, including mitochondrial proteins. Patients with the most severe disease had the lowest levels of Tau-interacting proteins, suggesting that the finding they made in neurons is relevant to human patients.

Dr. Gan and his team will next investigate whether strategies that elevate mitochondrial Tau interactions could enhance energy metabolism to counteract the effects of pathogenic Tau. They are also studying what cellular processes allow toxic versions of Tau to spread through synapses into the brain to see if they can be stopped. Dr. Gan also believes his team’s research could help scientists develop new biomarkers to detect early signs of mitochondrial dysfunction, allowing clinicians to intervene earlier in the course of the disease.

“The Tau interactome atlas provides an exciting roadmap for the scientific community to explore new therapeutic targets and biomarkers for Alzheimer’s disease and related dementia,” said Dr. Gan.

Reference: Tracy TE, Madero-Pérez J, Swaney DL, et al. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell. 2022;0(0). doi:10.1016/j.cell.2021.12.041

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