Mapping dementia-linked protein interactions

By mapping all the interactions of a dementia-linked protein in the brain called tau, investigators at Weill Cornell Medicine have created a roadmap for identifying potential new treatment targets for Alzheimer’s disease and related dementia.

Tau protein has long been implicated in neurodegenerative diseases. Mutations in the gene that encodes the tau protein result in neurodegenerative conditions like 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, Dr Li Gan and her colleagues created a comprehensive atlas, called a Tau interactome, that maps all the tau protein’s interactions with other proteins in human neurons grown in the laboratory. Dr Gan noted, “Tau is at the centre of neurodegeneration, and understanding how it causes toxicity and cognitive decline has the potential to lead to new therapies to treat dementia.”

The team’s results, published in the journal Cell, reveal that mutations that diminish the interactions between tau and mitochondrial proteins may hamper energy production in the brain, the most energy-intensive organ in the body. Additionally, they found that tau interacts with proteins in the synaptic sites that send electric signals to other neurons, which may provide clues on how toxic tau protein spreads in brains with tau pathology.

In normal and diseased neurons, tau protein forms physical interactions with specific proteins to participate in diverse neuronal functions. To develop an atlas that maps the interactions modified by disease-causing mutations and neuronal activity, Dr Gan and colleagues grew human neurons from induced pluripotent stem cells that carry normal tau gene or tau gene with mutations that cause frontotemporal dementia. They used a technique called quantitative affinity purification–mass spectrometry (AP–MS), which enables the study of protein interactions, to compare how normal and disease-causing mutants of tau behave. To capture how neuronal activity alters the tau interactome, they used a cutting-edge technology called engineered ascorbic acid peroxidase (APEX) to label proteins in close proximity to tau within milliseconds.

“The combination of two highly quantitative proteomic technologies has allowed us to establish Tau interactions with unprecedented spatial and time resolution in human neurons,” Dr Gan said.

Unexpectedly, the team discovered that tau interacts with proteins that are released into the synapses that send signals to neighbouring neurons. This may allow disease-causing versions of tau to spread from one region of the brain to another and help explain the phenomenon that neurons that fire together often die together, Dr Gan said.

Another surprise finding is that tau proteins have strong interactions with many proteins in the energy-producing mitochondria of neurons. According to Dr Gan, “More and more studies link dysregulated energy metabolism with neurodegeneration, but the mechanism remains elusive. We found disease-causing mutations reduce tau–mitochondrial protein interaction and impair mitochondrial function.”

When they analysed patient data from the Accelerating Medicines Partnership Program for Alzheimer’s Disease (AMP AD), Dr Gan and her team found that patients with Alzheimer’s disease had lower levels of tau-interacting proteins, including mitochondria proteins. Patients with the most severe disease had the lowest levels of tau-interacting proteins, suggesting that the discovery they made in neurons is relevant to human patients.

The team will next investigate if strategies elevating mitochondria–tau interactions could enhance energy metabolism to counteract the effects of disease-causing tau protein. They are also studying which cellular processes allow toxic versions of tau to spread throughout the brain via the synapses to see if they can be stopped. Dr Gan also thinks her team’s research may help scientists develop novel biomarkers to detect the early signs of mitochondrial dysfunction, allowing clinicians to intervene earlier in the course disease.

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

Image credit: ©stock.adobe.com/au/VFX

Please follow us and share on Twitter and Facebook. You can also subscribe for FREE to our weekly newsletters and bimonthly magazine.