Researchers Uncover New Details Behind Alzheimer’s Using Cryo-EM and Mass Spectrometry

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Tau protein is associated with causing Alzheimer’s and other neurodegenerative brain diseases. However, it has been difficult for scientists to pinpoint exactly why these proteins can cease their usual protective function and end up aggregating to form large tangles that cause the damaged cells seen in the brains of dementia patients.

In an exciting study published in Cell on February, 6, 2020, researchers at Columbia University’s Zuckerman Institute in New York and Mayo Clinic in Florida succeeded in mapping the tau protein in unprecedented detail by using two complementary techniques: cryo-electron microscopy (cryo-EM) and mass spectrometry.

Using our Thermo Scientific Krios Cryo-TEM with our Thermo Scientific Orbitrap Fusion Lumos Tribrid Mass Spectrometer, the researchers discovered that modifications to the tau protein may affect the different ways the protein can misfold in a person’s brain cells. These differences are closely related to both the type of neurogenerative disease that will develop and how quickly the disease will spread throughout the brain. The study maps the structure of tau, while uncovering the effects of additional molecules, known as post-translational modifications (PTMs), on the surface of the tau protein.

“The brains of patients with neurodegenerative diseases are easy to identify: entire sections have been eaten away, replaced by large clumps and tangles of misfolded proteins like tau,” says Tamta Arakhamia, an undergraduate student at Columbia University and one of the study’s authors. “But tau filaments are 10,000 times thinner than the width of a human hair, making them extraordinarily difficult to study in detail.”

3D visualization of Tau filaments 503L

3D visualization of Tau filaments 503L.

In recent years, an increasing number of researchers have turned to the complementary methods of cryo-EM and mass spectrometry to characterize different proteins and protein complexes. By combining these two cutting-edge techniques, scientists have been able to collect chemical information via mass spectrometry that can be combined with the structural cryo-EM data to provide a more complete insight that would not be possible with cryo-EM alone.

Using cryo-EM in parallel with mass spectrometry, the research team discovered that PTMs may be serving as markers on the surface of the protein and influencing the behavior of the tau. The findings may inspire new approaches for designing diagnostic tools and drugs that could slow the progression of Alzheimer’s and a host of other debilitating brain diseases.

“Neurogenerative diseases are perhaps the most complex and distressing class of illnesses, but through our work and the work of our colleagues and collaborators, we are building a solid roadmap toward successful diagnostics and therapeutics,” commented Anthony Fitzpatrick, Ph.D., a principal investigator at Columbia’s Zuckerman Institute who led the study.

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