Journal News

Protein that can be toxic in heart and nerves may help prevent Alzheimer's

University of Texas Southwestern Medical Center
By University of Texas Southwestern Medical Center
March 26, 2021

A protein that wreaks havoc in the nerves and heart when it clumps together can prevent the formation of toxic protein clumps associated with Alzheimer's disease, a new study led by a University of Texas Southwestern researcher shows. The findings, published in the Journal of Biological Chemistry, could lead to new treatments for this brain-ravaging condition, which currently has no truly effective therapies and no cure.

Researchers long have known that sticky plaques of a protein known as amyloid beta are a hallmark of Alzheimer's and are toxic to brain cells. As early as the mid-1990s, other proteins were discovered in these plaques as well.

One of these, a protein known as transthyretin, or TTR, seemed to play a protective role, explained Lorena Saelices, assistant professor of biophysics at the Center for Alzheimer's and Neurodegenerative Diseases at UTSW, a center that is part of the Peter O'Donnell Jr. Brain Institute. When mice modeled to have Alzheimer's disease were genetically altered to make more TTR, they were slower to develop an Alzheimer's-like condition; when they made less TTR, they developed the condition faster.

JBC-amyloid-beta-720x333.jpg
UTSW Medical Center
Abnormal deposits of the protein amyloid beta in the brain have been linked to Alzheimer's disease. The above illustration reveals a potential
way discovered by UTSW researchers to stop this process, leveraging the protective nature of the protein transthyretin (TTR) to identify a segment
of this protein, TTR-S, that halts plaque formation and facilitates its degradation in a test tube.

In healthy people and animals, Saelices said, TTR helps transport thyroid hormone and the vitamin A derivative retinol to where they're needed in the body. For this job, TTR forms a tetramer — a shape akin to a clover with four identical leaflets. However, when it separates into molecules called monomers, these individual pieces can act like amyloid beta, forming sticky fibrils that join together into toxic clumps in the heart and nerves to cause the rare disease amyloidosis. In this condition, amyloid protein builds up in organs and interferes with their function.

Saelices wondered whether there might be a connection between TTR's separate roles in both preventing and causing amyloid-related diseases. "It seemed like such a coincidence that TTR had such opposing functions," she said. "How could it be both protective and damaging?"

To explore this question, she and her colleagues developed nine different TTR variants with differing propensities to separate into monomers that aggregate, forming sticky fibrils. Some did this quickly, over the course of hours, while others were slow. Still others were extremely stable and didn't dissociate into monomers at all.

When the researchers mixed these TTR variants with amyloid beta and placed them on neuronal cells, they found stark differences in how toxic the amyloid beta remained. The variants that separated into monomers and aggregated quickly into fibrils provided some protection from amyloid beta, but it was short-lived. Those that separated into monomers but took longer to aggregate provided significantly longer protection. And those that never separated provided no protection from amyloid beta at all.

Saelices and her colleagues suspected that part of TTR was binding to amyloid beta, preventing amyloid beta from forming its own aggregations. However, that important piece of TTR seemed to be hidden when this protein was in its tetramer form. Sure enough, computational studies showed that a piece of this protein that was concealed when the leaflets were conjoined could stick to amyloid beta. However, this piece tended to stick to itself to quickly form clumps. After modifying this piece with chemical tags to halt self-association, the researchers created peptides that could prevent the formation of toxic amyloid beta clumps in solution and even break apart preformed amyloid beta plaques. The interaction of modified TTR peptides with amyloid beta resulted in the conversion to forms called amorphous aggregates that were broken up easily by enzymes. In addition, the modified peptides prevented amyloid seeding, a process in which fibrils of amyloid beta extracted from Alzheimer's disease patients can act as a template in the formation of new fibrils.

Saelices and her colleagues are currently testing whether this modified TTR peptide can prevent or slow progression of Alzheimer's in mouse models. If they're successful, she said, this protein snippet could form the basis of a new treatment for this recalcitrant condition.

"By solving the mystery of TTR's dual roles," she said, "we may be able to offer hope to patients with Alzheimer's."

University of Texas Southwestern Medical Center
University of Texas Southwestern Medical Center

The University of Texas Southwestern Medical Center integrates pioneering biomedical research with exceptional clinical care and education. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research to new clinical treatments.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

DNA and COVID-19: What’s the connection?
Observance

DNA and COVID-19: What’s the connection?

April 23, 2021

Studies have linked virus susceptibility and severity to genes inherited from Neanderthals and to blood type — but not all researchers agree on the results.

A celebration of our other genome: Mitochondrial DNA
Observance

A celebration of our other genome: Mitochondrial DNA

April 22, 2021

The genes in human mtDNA encode some essential components of the electron transport chain, as well as a set of tRNAs and ribosomal RNAs necessary for protein synthesis.

Eternal memories and an overdue tribute — storing digital data in DNA
Art

Eternal memories and an overdue tribute — storing digital data in DNA

April 21, 2021

Researchers crowdsourced 10,000 images, stored them on synthetic DNA and then used them to create a portrait of Rosalind Franklin, an often overlooked star of DNA discovery.

Genetic research in the midst of a pandemic
Observance

Genetic research in the midst of a pandemic

April 20, 2021

A study in the United Kingdom has identified four novel genetic variants associated with critical illness in patients with COVID-19.

Scientists unmask a virus that mimicked human RNA and hit on a potential vaccine
News

Scientists unmask a virus that mimicked human RNA and hit on a potential vaccine

April 18, 2021

Human metapneumovirus is a molecular mimic, sneaking past immune systems to cause cold symptoms

Synthesis of potent antibiotic follows unusual chemical pathway
News

Synthesis of potent antibiotic follows unusual chemical pathway

April 17, 2021

Images of a protein involved in creating a potent antibiotic reveal the unusual first steps of the antibiotic's synthesis.