Transthyretin Protein Could Prevent Alzheimer, Despite Dangers in Heart and Lungs

Although transthyretin can play a negative role in patients with amyloidosis, it may have protective effects in patients with Alzheimer disease.

New research suggests that transthyretin (TTR), a protein that can be toxic in the heart and nerves, may be able to prevent the formation of toxic protein clumps associated with Alzheimer disease. The findings could potentially lead to new treatments for the condition, according to the study, published in the Journal of Biological Chemistry.

Earlier research has shown that the plaques of the amyloid beta protein are a hallmark of Alzheimer and are toxic to brain cells. As early as the mid-1990s, investigators found other proteins in these plaques as well, including TTR, which seems to play a protective role.

In healthy people, TTR helps transport thyroid hormone and retinol to where they’re needed in the body, according to researcher Lorena Saelices, PhD, an assistant professor of biophysics at the University of Texas Southwestern. In order to do this, TTR forms a tetramer, although the individual pieces can act like amyloid beta when it separates into molecules called monomers, forming sticky fibrils in the heart and nerves, which cause amyloidosis. For patients with amyloidosis, amyloid protein builds up in organs and interferes with their function, according to the study.

Saelices investigated 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 in the press release. “How could it be both protective and damaging?”

To answer that question, she and her colleagues developed 9 different TTR variants with differing propensities to separate into monomers that aggregate, forming sticky fibrils. Some variants did this quickly over several hours, whereas others were slow. Some were extremely stable and did not dissociate into monomers at all.

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

The investigators suspected that part of TTR was binding to amyloid beta, preventing it from forming its own aggregations. However, that important piece of TTR seemed to be hidden when the protein was in its tetramer form. Computational studies showed that a piece of the protein that was concealed when the leaflets were conjoined could stick to amyloid beta. However, this piece tended to stick to itself and quickly form clumps, according to the study.

After modifying this piece with chemical tags to prevent self-association, the investigators created peptides that could prevent the formation of toxic amyloid beta clumps in solution and even break apart preformed plaques. The interaction of modified TTR peptides with amyloid beta resulted in a conversion to amorphous aggregates that were easily broken up by enzymes.

Furthermore, the modified peptides prevented amyloid “seeding,” a process in which fibrils of amyloid beta extracted from patients with Alzheimer can template the formation of new fibrils.

The investigators are currently testing whether this modified TTR peptide can prevent or slow progression of Alzheimer in mouse models, and they hope that this protein snippet could form the basis of a new treatment for Alzheimer disease.

“By solving the mystery of TTR’s dual roles, we may be able to offer hope to patints with Alzheimer’s,” Saelices concluded in the press release.

REFERENCE

Protein that can be toxic in the heart and nerves may help prevent Alzheimer’s [news release]. EurekAlert; January 7, 2021. https://www.eurekalert.org/pub_releases/2021-01/usmc-ptc010721.php. Accessed April 22, 2021.