ADVERTISEMENT
Protein Variant Offers Hope for Alzheimer’s Disease Treatment
The protein transthyretin (TTR) may play a role in the development of new treatments for Alzheimer’s disease by preventing the formation of amyloid beta clumps, according to a study published in the Journal of Biological Chemistry.
Found in amyloid beta clumps, TTR has previously demonstrated an apparent protective effect against the development of Alzheimer’s disease. Mouse studies have shown that animals with more TTR are slower to develop Alzheimer’s-like symptoms, while those with less TTR develop the condition more quickly, researchers explained
Investigational Antibody May Slow Cognitive Decline in Patients With Alzheimer's
The new research discovery involves what researchers consider opposing functions of TTR. In healthy individuals, TTR forms a tetramer, a clover-resembling shape with 4 identical leaflets, to help transport thyroid hormone and the vitamin A derivative retinol throughout the body. But when the protein separates into molecules called monomers, TTR can form sticky fibrils, create toxic clumps in the heart and nerves, and interfere with organ function—a disease known as amyloidosis.
For this study, researchers created 9 variants of TTR. Some separated into monomers and formed sticky fibrils quickly, while others did so slowly, and some did not dissociate into monomers at all. They then mixed the TTR variants with amyloid beta and placed them on neuronal cells. TTR that separated into monomers but took some time to aggregate and form sticky fibrils provided the best protection from amyloid beta, researchers reported.
Computational studies revealed that a piece of TTR, concealed when leaflets were conjoined, stuck to amyloid beta when separated into monomers. Researchers modified the piece with chemical tags to prevent it from sticking to itself and forming clumps, then created peptides that prevented formation of amyloid beta clumps and even broke apart amyloid beta plaques in solution. What’s more, the modified peptides prevented amyloid seeding, a process in which amyloid beta fibrils extracted from people with Alzheimer’s disease can template the formation of new fibrils, researchers explained.
The research team is currently testing whether the modified TTR peptide slows, or even prevents, the progression of Alzheimer’s in mouse models.
“By solving the mystery of TTR’s dual roles, we may be able to offer hope to patients with Alzheimer’s,” said researcher Lorena Saelices, PhD, an assistant professor of biophysics at UT Southwestern Medical Center, Dallas, Texas.
—Jolynn Tumolo
References
