A protein implicated in producing aggregates harmful to the body may protect against Alzheimer’s. Ongoing research into how this mechanism might work has led one team of researchers to the verge of creating a new drug to prevent or delay Alzheimer’s symptoms.
Transthyretin (TTR) is a protein that acts as a transporter, carrying vitamin A and the hormone thyroxine through the body via cerebrospinal fluid and the bloodstream. TTR is mostly produced in the liver and in the brain regions where cerebrospinal fluid is made, although recent studies have found that it can be produced at low levels in neurons.
To act efficiently as a transporter, TTR forms a structure called a “tetramer” comprised of four subunits. However, these tetramers can break down in people carrying a TTR gene mutation, and in old people. When this happens, the subunits of the tetramer fold into tough aggregates called amyloids, which accumulate in the heart, kidneys, peripheral nerves and elsewhere.
Build-ups of these amyloids are associated with familial amyloid polyneuropathy and senile systemic (cardiac) amyloidosis – diseases that are known to shorten lifespan.
In the mid-1990s, reports began to emerge that TTR was able to bind to amyloid-beta, the protein associated with Alzheimer’s, and prevent it from aggregating. If correct, these reports would suggest that TTR may protect against Alzheimer’s.
The Scripps Research Institute’s Prof. Joel N. Buxbaum, co-author of the new study, was skeptical.
“At the time it seemed unlikely that one amyloidogenic precursor would have a beneficial effect on the aggregation of another,” he told Medical News Today. “The in vitro experiments were technically suspect, but turned out to be essentially correct. ”
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Following the initial report of the link in 1995, Prof. Buxbaum points out the laboratory in question did not publish any further papers on the subject for another 10 years, suggesting that the results might not be reproducible.
“Given that background, I was predisposed to be skeptical,” he told us, “which was probably a good thing since it made me look at the data from our genetic experiments very critically. I figured if the results convinced me, they should convince anyone.”
However, in a 2008 study, Prof. Buxbaum and colleagues expanded their current work on TTR amyloidoses to test the Alzheimer’s theory. In transgenic mice bred to overproduce amyloid-beta – and so display symptoms of Alzheimer’s – Buxbaum’s team experimented with also overproducing TTR.
It worked. The team found that the TTR reduced the aggregating amyloid-beta in the mice’s brains and improved their memory.
Subsequent studies by Buxbaum’s team further probed the TTR’s binding mechanism and how this prevents amyloid-beta from forming harmful aggregates in the brain.
In their latest study, Prof. Buxbaum and lead authors Xin Wang and Francesca Cattaneo analyzed DNA near the TTR gene. The researchers wondered whether transcription factors – special DNA-binding proteins produced in “the promoter region” – could increase activity of the TTR gene.
One of these transcription factors, Heat Shock Factor 1 (HSF1), was able to bind to the promoter of the TTR gene, boosting TTR production.
Interestingly, this boost in TTR production could only occur in neuronal-type cells and not in the liver cells where the bulk of the body’s TTR is produced. In fact, HSF1 seemed to slightly decrease TTR production in liver cells.
“This result was completely unexpected when we started this research,” says Prof. Buxbaum. “But now we realize that it could indicate a new approach for Alzheimer’s prevention and therapy.”
To examine how this might apply to Alzheimer’s, the researchers compared a group of transgenic “Alzheimer’s mice” with a group of ordinary lab mice. They found that the frequency of HSF1 binding to the TTR gene promoter was doubled in the Alzheimer’s mice.
This has led the team to the early stages of developing a small molecule compound that could be delivered in a pill. This compound would modestly boost HSF1 activity and TTR production in neurons in order to prevent or delay the symptoms of Alzheimer’s.
Medical News Today recently reported on another study that looked at amyloid-beta’s influence on Alzheimer’s in a mouse model. Administering the mice with a compound to regulate production of amyloid-beta, the researchers behind that study reported promising results in “reversing” the symptoms of Alzheimer’s.