Editor: Akhmetova Aigerim
Author: Bolysbek Dana
It was previously known that sticky plaques of a protein known as beta-amyloid are a sign of Alzheimer's disease and are toxic to brain cells. Back in the mid-1990s, other proteins were found in these plaques.
One of them, a protein known as transthyretin (TTR), appears to play a protective role. In healthy humans and animals, TTR helps transport thyroid hormone and retinol, a derivative of vitamin A. To do this, TTR forms a tetramer - a form similar to a clover with four identical leaves. However, when it splits into molecules called monomers, these individual parts can act as beta-amyloid, forming sticky fibrils that combine to form toxic clusters in the heart and nerves, causing the rare disease amyloidosis. In this state, amyloid protein accumulates in the organs and disrupts their function.
Lorena Saelis, Ph. D., associate professor of Biophysics at the UTSW Center for Alzheimer's and Neurodegenerative Diseases, asked if there was a link between the individual roles of TTR in both the prevention and occurrence of amyloid-related diseases.
To study this question, she and her colleagues developed nine different TTR variants with different propensities for splitting into monomers that combine to form sticky fibrils. Some did it quickly, within a few hours, others slowly. Still others were extremely stable and did not dissociate into monomers at all.
When the researchers mixed these TTR variants with beta-amyloid and placed them on neuronal cells, they found dramatic differences in beta-amyloid toxicity. Variants that split into monomers and rapidly aggregate into fibrils provide some protection against beta-amyloid, but it does not last long. Those that split into monomers but took longer to assemble provided significantly longer protection. And those who have never been separated, did not provide any protection from beta-amyloid.
Salis and her colleagues suspected that part of TTR binds to beta-amyloid, preventing the formation of its own clusters of beta-amyloid. However, this important part of TTR was hidden when this protein was in tetrameric form. Computer studies have shown that the part of this protein that was hidden could stick to beta-amyloid.
However, this piece tended to stick to itself and quickly form lumps. After modifying this fragment with chemical labels to stop sticking, the researchers created peptides that can prevent the formation of toxic accumulations of beta-amyloid in solution and even destroy pre-formed beta-amyloid plaques. The interaction of the modified TTR peptides with beta-amyloid led to the transformation into forms called amorphous aggregates, which are easily destroyed by enzymes. In addition, the modified peptides prevent amyloid "seeding", a process in which beta-amyloid fibrils extracted from Alzheimer's patients can template the formation of new fibrils.
Salis and her colleagues are currently testing this peptide in mouse models. If they are successful, she says, this protein could form the basis of a new treatment for Alheimer's disease.
"By solving the mystery of the dual role of TTR," she says , " we can give hope to Alzheimer's patients."